Liver reprogramming toward hepatocellular carcinoma following hepatitis C sustained virologic response: a narrative review

Introduction

Hepatitis C virus (HCV) infection has historically been a primary driver of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) worldwide (1). For decades, the standard of care relied on interferon (IFN)-based regimens associated with significant toxicity and suboptimal cure rates. The advent of direct-acting antivirals (DAAs) marked a paradigm shift in hepatology, offering a well-tolerated, oral treatment with efficacy exceeding 95% across multiple genotypes (2-5). DAA therapy has substantially reduced all-cause mortality, from 10.33 deaths per 100 person-years in untreated patients to approximately 1.07 following sustained virologic response (SVR) (6). Yet the widespread success of DAAs has unveiled a sobering clinical reality: virologic cure, defined as SVR, is not equivalent to biological cure of the liver. Longitudinal epidemiological studies consistently demonstrate that although SVR reduces the relative risk of HCC, the absolute risk remains clinically significant, particularly in patients with pre-existing advanced fibrosis (F3) or cirrhosis (F4) (7). The continued annual HCC incidence of 1.0–3.0% among cured patients, far exceeding that of the general population, underscores the need for ongoing lifelong surveillance and mechanistic investigation (8-10). This persistent oncogenic risk implies that once initiated, virus-driven carcinogenic processes can become self-sustaining and uncoupled from the continued presence of the pathogen.

The post-SVR landscape is further complicated by the rising global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). In the absence of active viral replication, metabolic factors, including obesity, type 2 diabetes mellitus (T2DM), and insulin resistance, emerge as dominant drivers of ongoing liver injury (11). Epidemiological data increasingly point toward a “synergistic hepatocarcinogenesis”: the residual molecular damage left by HCV creates a permissive soil that is substantially more vulnerable to metabolic insults. Patients with a history of HCV cure who harbor concurrent MASLD or T2DM exhibit a markedly higher HCC risk than those with viral clearance alone.

Despite this clinical evidence, the molecular basis of this residual and synergistic risk remains incompletely understood. Current guidelines focus on virologic endpoints, yet no framework exists to quantify or monitor the durable oncogenic molecular alterations that may persist after SVR, alterations operating independently of active viral replication. This constitutes a critical knowledge gap that limits both risk stratification and the rational design of chemopreventive interventions in the post-DAA era.

This narrative review proposes, based on available associative evidence, that HCV infection may induce a lasting reconfiguration of the hepatic microenvironment, an “oncogenic memory”, driven by four interconnected pillars of molecular scarring: epigenetic, metabolic, immunological, and stromal. By systematically dissecting these mechanisms and their synergistic amplification by MASLD, this review aims to: (I) provide a unified molecular framework explaining why HCC risk persists despite virologic cure; (II) identify the highest-risk patient subpopulations warranting intensified surveillance; and (III) highlight rational molecular targets for future chemoprevention trials. Ultimately, this work advocates that the clinical definition of “cure” in the post-DAA era must evolve to encompass biological and molecular remission, not virologic clearance alone. We present this article in accordance with the Narrative Review reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0031/rc).

Methods

A narrative literature search was conducted across three major databases—PubMed/MEDLINE, Scopus, and Web of Science, for articles published between January 2015 and December 2025. The literature search incorporated combinations of terms related to the disease context (hepatitis C virus or HCV), treatment outcome (sustained virologic response or SVR), and oncologic complication (hepatocellular carcinoma or HCC). These were further combined with specific pathway identifiers: epigenetic, metabolic reprogramming, immune exhaustion, fibrosis, and lysyl oxidase-like 2 (LOXL2). Following deduplication, titles and abstracts were independently screened by two authors (D.H.H.L. and P.N.) for relevance to the four core themes of this review; discrepancies were resolved by consensus with senior authors (Y.P. and S.H.). Studies were included if they provided original mechanistic data from human post-SVR tissue, outcomes from prospective or retrospective clinical cohorts, validated animal or cell-line models, or relevant meta-analyses in adult populations. Additional references were identified through manual bibliography screening of selected articles. Case reports, editorials, conference abstracts, and non-peer-reviewed sources were excluded. The complete search strategy summary is presented in Table 1.

Epigenetic scarring: the chromatin basis of oncogenic memory

Among the most extensively characterized layers of post-SVR oncogenic risk is epigenetic reprogramming, a layer that is mechanistically compelling but for which causal validation in prospective human cohorts remains an outstanding priority. Epigenetic modifications regulate gene expression without altering the DNA sequence, and they serve as the cellular “memory” of past environmental states (12). Chronic HCV infection induces profound changes in the host chromatin landscape, many of which fail to revert following viral eradication.

The H3K27ac signature: a marker of aberrant enhancers

Genome-wide profiling of histone modifications has provided breakthrough insights into the post-SVR liver. Specifically, the acetylation of lysine 27 on histone H3 (H3K27ac) is a critical marker associated with active promoters and, more importantly, active enhancers (7,13). Enhancers are distal regulatory elements that loop to gene promoters to drive high-level transcription, often determining cell identity and state.

Seminal work comparing liver tissues from chronic HCV patients, DAA-cured patients, and uninfected controls revealed that HCV infection is associated with a specific, genome-wide redistribution of H3K27ac (7). Strikingly, in patients who achieved SVR, the global H3K27ac profile showed limited reversion toward a ‘healthy’ baseline in several studies, clustering more closely with the profile of active chronic infection, though the causal relationship between this epigenetic persistence and clinical HCC risk requires prospective validation (14). This persistence indicates that the virus leaves behind an “epigenetic scar”, a locked chromatin state that continues to drive the expression of pro-oncogenic genes long after the viral trigger is removed (12,15).

The stability of these epigenetic marks suggests a failure in the chromatin remodeling machinery to “reset” the liver’s program. During infection, HCV proteins (such as Core and NS5A) recruit histone acetyltransferases (like p300/CBP) to specific loci to facilitate viral replication or host survival (16). Upon viral cure, the absence of active viral proteins should theoretically allow histone deacetylases (HDACs) to remove these marks. The fact that H3K27ac persists suggests that the chromatin landscape has crossed a “bifurcation point” into a stable, alternative state, potentially maintained by the recruitment of bromodomain and extraterminal (BET) proteins like BRD4, which bind acetylated histones and perpetuate the open chromatin structure (12). Consequently, this sustained open chromatin architecture renders oncogenic loci highly accessible, thereby facilitating their aberrant transcriptional activation.

The “HCC high-risk” gene signature

This epigenetic scarring is not random; it specifically affects pathways associated with neoplasia, cell cycle progression, and lipid metabolism. Transcriptomic integration with ChIP-seq data has identified a robust gene signature driven by these aberrant enhancers (7,17).

One of the most biologically significant targets identified is sphingosine kinase 1 (SPHK1). The H3K27ac signal at the SPHK1 enhancer remains significantly elevated post-SVR, correlating with sustained overexpression of SPHK1 mRNA and protein (18). However, it must be noted that the majority of these findings derive from a single landmark study (7) and require independent replication in larger, multi-ethnic cohorts (12). As detailed in the following section on metabolic reprogramming, SPHK1 is the rate-limiting enzyme in the production of sphingosine-1-phosphate (S1P), a potent bioactive lipid which promotes survival, proliferation, and angiogenesis (19). As detailed in Figure 1, persistent H3K27ac at the SPHK1 enhancer may provide a mechanistic link between the viral scar and the persistent metabolic deregulation observed in these patients.

Figure 1 HCV-associated epigenetic changes at the SPHK1 locus and their association with metabolic reprogramming and genomic instability. Created on https://BioRender.com/q13c0pm. (A) Epigenetic primer: post-SVR, the SPHK1 locus retains a persistent open chromatin state characterized by H3K27ac enrichment (green flags) and BRD4 recruitment, facilitating sustained transcription by RNA Polymerase II. (B) Metabolic engine: upregulated SPHK1 produces S1P, which activates the S1PR1-PI3K-AKT-mTORC1 axis. This signaling cascade inhibits GSK-3β, thereby blocking the proteasomal degradation (red cross) of SREBP1c. Stabilized SREBP1c induces lipogenic genes (ACC, FASN), involved with lipid accumulation, elevated NADH, and ROS production (purple lightning) that linked to genomic instability. ACC, acetyl-CoA carboxylase; AKT, protein kinase B; BRD4, bromodomain-containing protein 4; FASN, fatty acid synthase; GSK-3β, glycogen synthase kinase-3 beta; H3K27ac, Histone H3 Lysine 27 acetylation; HCV, hepatitis C virus; mTORC1, mammalian target of rapamycin complex 1; NADH, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate; S1PR1, sphingosine-1-phosphate receptor 1; SPHK1, sphingosine kinase 1; SREBP1c, sterol regulatory element-binding protein 1c; SVR, sustained virologic response.

The epigenetic scar also encompasses genes such as WNT10A, a ligand for the Wnt/beta-catenin pathway, and JUNB, a component of the AP-1 transcription factor complex (20,21). The sustained expression of WNT10A correlates with enhanced cell cycle entry and regeneration, creating a state of “pseudo-proliferation” that increases the likelihood of fixing random mutations into the genome. Additionally, genes related to inflammatory signaling, such as EDN1 (endothelin-1), show persistent epigenetic activation, potentially contributing to a pro-inflammatory microenvironment (22).

Diagnostic markers and therapeutic implications

The irreversibility of these changes raises the possibility of using epigenetic markers for risk stratification. Patients with high levels of the “HCV scar signature” [e.g., high SPHK1 or WNT10A expression in liver biopsies or peripheral blood mononuclear cells (PBMCs)] may represent the sub-population at highest risk for HCC (9,22). Furthermore, preclinical models have shown that treatment with epigenetic inhibitors, such as BET inhibitors (targeting BRD4) or p300/CBP inhibitors, can revert the H3K27ac signature and reduce HCC risk, pointing toward a potential avenue for chemoprevention in the post-SVR setting (14,23,24).

Metabolic reprogramming: the SPHK1-SREBP axis and reductive stress

The liver is the central hub of systemic metabolism, and HCV is uniquely adapted to hijack this machinery. The “epigenetic scar” described above ensures that key metabolic enzymes remain dysregulated post-cure. This section explores how the sustained overexpression of SPHK1 is associated with a cascade of lipid anomalies and oxidative stress, creating a “metabolic addiction” that favors malignancy.

The sphingolipid rheostat: SPHK1 and S1P signaling

Sphingolipids are structural components of cell membranes and potent signaling molecules. The “sphingolipid rheostat” determines cell fate: ceramide and sphingosine promote apoptosis and growth arrest, whereas sphingosine-1-phosphate (S1P) promotes survival, proliferation, and metastasis (19).

In the post-SVR liver, the epigenetically driven upregulation of SPHK1 shifts this rheostat decisively toward S1P production. S1P exerts its oncogenic effects through two primary mechanisms:

• Receptor-mediated signaling (inside-out): S1P is secreted and binds to G-protein coupled S1P receptors (S1PR1, S1PR2) on the hepatocyte surface in an autocrine or paracrine manner. This activates the PI3K/AKT and MAPK/ERK signaling cascades, which are fundamental drivers of cell growth and survival (19);
• Intracellular signaling: S1P can also act as an intracellular second messenger, directly modulating the activity of enzymes involved in chromatin remodeling (such as HDACs) and metabolic regulation (19).

The SPHK1-SREBP1c axis: fueling de novo lipogenesis (DNL)

Based on mechanistic data from cell lines and experimental HCV infection models, a plausible downstream consequence of sustained SPHK1/S1P signaling involves the activation of SREBP1c through the PI3K/AKT/mTOR axis. While this axis is well-characterized in oncology, direct evidence of SPHK1-driven SREBP1c dysregulation in post-SVR human liver tissue remains limited and largely inferred from correlative transcriptomic data (25). SREBP1c is the master transcriptional regulator of DNL (25), controlling the expression of enzymes like acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) (26,27).

Under normal conditions, SREBP1c is tightly regulated and rapidly degraded. However, in the post-SVR liver, the SPHK1-S1P axis stabilizes SREBP1c through the PI3K/AKT/mTOR pathway (19):

• AKT activation: S1P-mediated activation of AKT leads to the inhibition of GSK-3β. GSK-3β normally phosphorylates SREBP1c to mark it for ubiquitination and proteasomal degradation (via the E3 ligase Fbw7). By inhibiting GSK-3β, the SPHK1 axis prevents SREBP1c degradation, extending its half-life (28);
• mTORC1 signaling: AKT activates mTORC1, which enhances the translation of SREBP1c mRNA and facilitates its processing from the endoplasmic reticulum (ER) to the nucleus (29).

As a consequence, SREBP1c stabilization results in continuous constitutive expression of lipogenic genes, promoting intracellular lipid accumulation (steatosis) independent of dietary intake (30,31). Thus, prior HCV infection is associated with persistent H3K27ac at the SPHK1 enhancer. This correlates with sustained SPHK1-S1P signaling, which is associated with reduced degradation and enhanced production of SREBP1c. This is linked to increased hepatic lipid production independent of dietary intake. The detailed mechanism is illustrated in Figure 1.

Reductive stress: the hidden metabolic danger

The consequences of unrestrained lipogenesis extend beyond simple fat storage. The synthesis of fatty acids is metabolically demanding and alters the cellular redox balance, leading to a state of reductive stress.

• Nicotinamide adenine dinucleotide (NADH) accumulation: metabolic flux through lipogenesis and associated glycolytic pathways can lead to NADH accumulation, thereby increasing the NADH/NAD⁺ ratio (32).
• Impaired sirtuin activity: high NADH levels inhibit sirtuins (specifically SIRT1), which require NAD⁺ as a cofactor. Sirtuins are critical guardians of genomic integrity; their inhibition results in the hyperacetylation of proteins involved in DNA repair and metabolism, thereby compromising genomic stability. This mechanism is distinctly exemplified by the HCV core protein, which alters the cellular redox state by decreasing the NAD⁺/NADH ratio. This redox shift modulates SIRT1 and, secondarily, AMPK activity, thereby reprogramming the expression of genes involved in glucose and lipid metabolism and ultimately inducing metabolic dysfunction in hepatocytes (33,34).
• Reactive oxygen species (ROS) generation: paradoxically, an excess of reducing equivalents (NADH) overloads the mitochondrial electron transport chain (specifically Complex I), causing electron leakage and the profound generation of superoxide and other ROS. Specifically, the HCV Core, E1, and NS3 proteins function as potent inducers of ROS, resulting in DNA damage and the subsequent activation of STAT3. Consistent with these findings, core-protein-transgenic mice exhibit elevated levels of lipid peroxidation and accumulation of oxidatively damaged DNA (35-37).

This establishes a vicious cycle wherein the ‘metabolic scar’ may contribute to lipogenesis, subsequently generating reductive stress and ROS. These ROS induce DNA damage (e.g., 8-oxo-dG accumulation) in hepatocytes that are forced to undergo compensatory proliferation, thereby significantly increasing the probability of malignant transformation. Crucially, this pathogenic loop is continuously sustained and amplified throughout the course of HCV infection, resulting in cumulative genomic instability (refer to Figure 1 for a detailed schematic) (37,38).

Synergistic hepatocarcinogenesis: the role of MASLD

These molecular mechanisms substantiate long-standing clinical observations from the non-A, non-B hepatitis era, during which hepatic steatosis was frequently identified in biopsy specimens. Indeed, HCV is now recognized not merely as a viral infection but as a distinct ‘metabolic liver disease’ that subverts host lipid metabolism and promotes insulin resistance (39,40). This virus-driven metabolic reprogramming mirrors the features of metabolic syndrome, thereby accounting for the high prevalence of hepatic steatosis even in the absence of conventional risk factors. The “metabolic scar” described above renders the post-SVR liver uniquely susceptible to a “second hit” from MASLD. In patients with obesity or T2DM, the influx of dietary lipids converges with the SREBP-driven endogenous lipid production.

• Lipotoxicity: the hepatocyte’s capacity to store neutral triglycerides in lipid droplets becomes overwhelmed, leading to the accumulation of toxic lipid species such as free palmitate, ceramides, and diacylglycerols (41). Experimental evidence further demonstrates that HCV infection renders cells more susceptible to the accumulation of a toxic lipid profile compared with their normal counterparts (42). These lipotoxic intermediates induce ER stress (the unfolded protein response) and mitochondrial dysfunction (43).
• Lipoapoptosis and inflammation: lipotoxicity triggers hepatocyte cell death (lipoapoptosis). The release of damage-associated molecular patterns (DAMPs) from dying cells recruits immune cells, particularly macrophages, thereby perpetuating a cycle of chronic inflammation (NASH) that promotes fibrosis and carcinogenesis (44). DAMPs also trigger inflammatory signaling pathways in response to viral pathogens, including HBV and HCV (45).
• Clinical correlation: this mechanism explains the epidemiological finding that the coexistence of obesity or diabetes and a history of HCV infection results in a supra-additive risk of HCC recurrence and mortality (11).

Immunological scarring: the failure of tumor surveillance

Under physiological conditions, the immune system acts as a sentinel, detecting and eliminating nascent transformed cells (immunosurveillance). In the post-SVR liver, however, the immune landscape remains profoundly dysfunctional. Chronic infection leaves an “immunological scar” that prevents the re-establishment of effective surveillance, allowing early tumors to escape and expand.

T cell exhaustion: the TOX-PD1 axis

Chronic antigen stimulation during HCV infection drives CD8⁺ T cells into a state of “exhaustion” characterized by the progressive loss of effector functions (cytotoxicity and cytokine production) and the upregulation of inhibitory receptors. Crucially, this state shows limited reversibility after viral cure in observational studies (46-48).

The high mobility group transcription factor TOX appears as a key regulator associated with T cell exhaustion (49). TOX is induced by chronic T-cell receptor (TCR) stimulation and initiates a specific epigenetic program that is distinct from that of effector or memory T cells (50).

• Epigenetic locking: TOX alters the chromatin accessibility at loci encoding inhibitory receptors, such as PDCD1 [programmed cell death protein 1 (PD-1)], thereby ensuring their sustained high expression. Even after the antigen (HCV) is eliminated by DAAs, the epigenetic imprint established by TOX remains (49).
• Mechanisms of dysfunction: TOX promotes the endocytic recycling of PD-1, maintaining high surface levels of the receptor (51). It also represses genes involved in stemness (such as TCF1), thereby preventing exhausted T cells from differentiating into functional memory cells. Ultimately, this loss of functional plasticity impairs the immune system’s ability to eliminate damaged or premalignant cell reservoirs, facilitating the survival of defective cells that would otherwise be targeted for removal.
• Surveillance failure: These “scarred” T cells (Tex) persist within the liver parenchyma. When hepatocytes undergo malignant transformation driven by the metabolic pressures described in the metabolic reprogramming section and present neoantigens, these T cells are unable to mount an effective cytotoxic response. High programmed death-ligand 1 (PD-L1) expression on Kupffer cells and tumor cells engages PD-1 on the Tex cells, delivering inhibitory signals that paralyze the antitumor response (52).

Importantly, not all studies support the notion of irreversible T cell exhaustion post-DAA. Wieland et al. demonstrated that TCF1⁺ progenitor exhausted T cells, capable of self-renewal, are maintained after HCV clearance (48). Furthermore, Apol et al.’s 2025 systematic review found partial functional restoration in some exhausted T cell subsets following successful DAA treatment (53). These data suggest a spectrum of reversibility dependent on the depth and duration of prior viremia, fibrosis stage, and individual immunogenetic background, a nuance that any risk stratification framework must accommodate.

Tissue-resident memory (TRM) cell perturbation

The liver hosts a specialized population of TRM T cells (CD69⁺ CD103⁺), which serve as the first line of defense against local threats. In patients who spontaneously resolve HCV, a robust and functional TRM population is established. In contrast, in chronic patients cured by DAAs, the TRM compartment is often defective (54-56).

• Phenotypic alterations: post-SVR TRM cells often retain an “exhausted-like” phenotype, expressing residual levels of PD-1 and TOX. They fail to produce adequate levels of IFN-γ and TNF-alpha upon stimulation (53).
• Metabolic competition: the microenvironment plays a crucial role in this process. T cells are metabolically demanding and depend on glucose for optimal effector function. In the lipid-rich, “metabolically scarred” liver, hepatocytes and emerging tumor cells avidly consume glucose while releasing lipids. This forces TRM cells to rely on fatty acid oxidation (FAO). However, under conditions of hypoxia and excessive lipid load, this metabolic shift promotes mitochondrial dysfunction and T cell apoptosis (57).

Natural killer (NK) cell dysfunction and “obesity”

NK cells are essential for controlling viral infections and limiting fibrosis through the elimination of activated hepatic stellate cells. However, their function is profoundly impaired in the post-SVR, steatotic liver.

• Lipid-associated dysfunction: NK cells express scavenger receptors (such as CD36) that facilitate lipid uptake from the microenvironment. In a liver affected by post-SVR steatosis or MASLD, NK cells accumulate excessive lipid droplets (58,59).
• Metabolic paralysis: this “obesity” of NK cells induces a state of “metabolic paralysis”, in which accumulated lipids disrupt immunological synapse formation and impair the trafficking of cytotoxic granules (granzyme and perforin) to the cell membrane. Consequently, their ability to lyse tumor cells is markedly reduced (59).
• TRAIL-mediated inflammation: rather than eliminating tumor cells, these dysregulated NK cells may shift toward a pro-inflammatory phenotype, secreting cytokines that exacerbate liver injury without clearing malignant targets. This contributes to the “second hit” of inflammation required for HCC progression (60,61).

In summary, the post-SVR liver is compromised by a multilayered ‘immunological scar’, in which epigenetic rigidity in T cells and metabolic paralysis in NK cells converge to undermine tumor surveillance. This systemic failure creates a permissive microenvironment that allows nascent transformed cells to evade immune elimination and progress toward malignancy. A detailed schematic of these immune defects and their downstream consequences is presented in Figure 2.

Figure 2 Immunological scarring and surveillance failure in the post-SVR liver. Created on https://BioRender.com/q0ez127. Chronic HCV antigen exposure induces upregulation of the transcription factor TOX (red arrows) in CD8⁺ T cells, establishing an exhausted phenotype characterized by high surface expression of PD-1. The interaction between PD-1 and PD-L1 on transformed hepatocytes (HCC) delivers an inhibitory signal that blocks granzyme release (red “T” bar), thereby preventing the cytotoxic elimination of the tumor. Concurrently, NK cells within the pro-tumorigenic microenvironment accumulate lipid droplets, leading to a state of “metabolic obesity.” This dysfunction impairs direct cytotoxicity and alters cytokine secretion (TRAIL, IFN-g), collectively enabling malignant cells to escape immune surveillance. HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IFN-g, interferon-gamma; NK, natural killer cell; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TOX, thymocyte selection-associated high mobility group box; TRAIL, TNF-related apoptosis-inducing ligand.

Stromal memory: mechanical stiffness and YAP/TAZ signaling

The extracellular matrix (ECM) is not merely an inert scaffold; it provides physical signals that regulate cell behavior. Chronic HCV infection leads to fibrosis, characterized by collagen deposition and liver stiffening. Although DAAs can induce fibrosis regression, as measured by histological staging, the composition and mechanical properties of the ECM may remain altered, a phenomenon known as “stromal memory”.

LOXL2 and the cross-linked matrix

LOXL2 is a copper-dependent amine oxidase that catalyzes the covalent cross-linking of collagen and elastin fibers. This cross-linking increases the tensile strength and stiffness of the ECM and renders it resistant to proteolytic degradation by matrix metalloproteinases (MMPs) (9,62).

• Persistence: a prospective study by Chida et al. (n=102) demonstrated that serum LOXL2 levels remained elevated in a subset of post-SVR patients who subsequently developed HCC (9). While suggestive, this finding is derived from a single-center Japanese cohort and requires confirmation in ethnically and clinically diverse populations before LOXL2 can be considered a validated predictive biomarker (62).
• Stiffness vs. quantity: even when collagen content decreases after SVR (reflecting fibrosis regression), the remaining collagen may be highly cross-linked and stiff. This “increased stiffness” acts as a persistent physical mutagen (63).

The YAP/TAZ mechanotransduction loop

Liver stiffness is sensed by hepatocytes and transduced into intracellular biochemical signals through the Hippo pathway effectors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with a PDZ-binding motif) (64).

• Mechanosensing: integrins on the hepatocyte surface detect the stiff ECM. This mechanical tension is transmitted via the cytoskeleton to the nucleus, promoting the nuclear translocation of YAP and TAZ (65).
• Oncogenic transcription: once in the nucleus, YAP/TAZ bind to TEAD transcription factors to drive the expression of a pro-proliferative and anti-apoptotic gene program (e.g., CTGF, Cyr61, survivin) (64,66).
• The feed-forward loop: crucially, YAP/TAZ can activate LOXL2 transcription, creating a dangerous positive feedback loop: stiff matrix→YAP/TAZ activation → LOXL2 expression → increased cross-linking → an even stiffer matrix. Specifically, LOXL2 secreted by hepatocytes into ECM functions similarly to a molecular staple, catalyzing covalent cross-links between collagen and elastin fibers and effectively ‘pinning’ matrix components together. This structural reinforcement dramatically increases liver stiffness, potentially exceeding critical thresholds (e.g., >12 kPa), thereby further propagating the fibrotic cycle (67).
• Drug resistance and stemness: Elevated YAP/TAZ activity confers “stem-like” properties on hepatocytes and has been shown to impair drug penetration into the liver parenchyma, creating a sanctuary for developing tumors (68,69).

Mechanical memory

The concept of ‘mechanical memory’ provides a crucial mechanistic explanation for the persistence of HCC risk despite the clinical regression of fibrosis following HCV clearance. Driven by the initial viral infection, the YAP/TAZ-LOXL2 axis promotes a persistent shift of the ECM into a state of pathological stiffness (>12 kPa) through irreversible cross-linking. Consequently, resident hepatocytes remain entrapped within a rigid signaling niche that mimics the biophysical environment of a tumor. This aberrant mechanotransduction lowers the energetic threshold required for malignant transformation, creating a permissive soil for carcinogenesis long after the viral trigger is removed (65,70). The molecular intricacies of this stromal memory and its self-perpetuating feedback loop are illustrated in Figure 3.

Figure 3 The molecular mechanism of HCV-induced stromal memory and the YAP/TAZ-LOXL2 feed-forward loop. Created on https://BioRender.com/h94ch88. HCV infection triggers the activation and nuclear translocation of the mechanotransducers YAP and TAZ (red upward arrows). Within the nucleus, the YAP/TAZ complex binds to TEAD transcription factors to drive the expression of pro-proliferative genes (CTGF, Cyr61) as well as the gene encoding LOXL2. The synthesized LOXL2 protein is secreted into the extracellular space, where it functions as a molecular “staple” (red pins), catalyzing the covalent cross-linking of collagen and elastin fibers. This structural reinforcement increases liver stiffness to pathological levels (>12 kPa), which is sensed by integrins and the actin cytoskeleton, thereby further activating YAP/TAZ. This process establishes a self-perpetuating positive feedback loop that maintains a pro-tumorigenic “mechanical memory” even in the absence of the virus. CTGF, connective tissue growth factor; Cyr61, cysteine-rich angiogenic inducer 61; HCV, hepatitis C virus; LOXL2, lysyl oxidase-like 2; mRNA, messenger RNA; TAZ, transcriptional co-activator with PDZ-binding motif; TEAD, TEA domain transcription factor; YAP, Yes-associated protein.

Integrated synthesis: a unified model of synergistic residual oncogenicity

The four mechanisms described above, epigenetic, metabolic, immunological, and stromal, do not operate in isolation. Rather, they interact as an integrated network that drives hepatocarcinogenesis in the post-SVR liver, which is summarized in Table 2. We propose the following unified model:

• The epigenetic primer: chronic HCV infection leaves a persistent H3K27ac mark on the SPHK1 enhancer.
• The metabolic engine: this epigenetic alteration is associated with elevated SPHK1 expression and increased production of S1P. S1P signaling activates the PI3K/AKT/mTOR pathway, which stabilizes SREBP1c, resulting in constitutive DNL that leads to steatosis, reductive stress (NADH accumulation), and ROS generation (the “oxidative trigger”).
• The mechanical enforcer: residual LOXL2 activity maintains ECM stiffness (mechanical memory). This stiffness activates YAP/TAZ, which cooperates with metabolic machinery to promote cell survival and further matrix stiffening.
• The immune void: as hepatocytes accumulate DNA damage from metabolic and oxidative stress, immune surveillance fails. T cells exhibit persistent exhaustion, potentially mediated by TOX (immunological scar), and NK cells are functionally impaired by lipid overload.
• The result: a “perfect storm” in which initiated cells proliferate unchecked within a permissive, nutrient-rich, mechanically stiff, and immune-silent microenvironment.

The synergistic amplifier: metabolic dysfunction in the post-DAA era

While the molecular “scars” described in the previous sections provide the oncogenic substrate, the current clinical landscape acts as a potent catalyst. The historical shift from IFN-based therapies to DAAs has fundamentally altered the demographic profile of the “cured” patients. Residual HCC risk is no longer driven solely by viral sequelae but is increasingly amplified by the rising tide of metabolic syndrome.

The demographic shift and the “second hit”

Patients achieving SVR via DAAs typically present with more advanced fibrosis and a significantly higher prevalence of metabolic comorbidities than IFN-cured cohorts from earlier eras. A comparative analysis highlighted a striking divergence: the prevalence of NAFLD/MASLD in DAA-induced SVR patients who developed HCC was 62%, compared with only 28% in the historical IFN-induced SVR group (P=0.026) (71). This comparison, however, is subject to important confounding factors: IFN-era cohorts were predominantly younger, leaner, and had shorter disease duration. Therefore, the observed difference in MASLD prevalence may simply reflect the broader epidemiological rise in metabolic syndrome over time, rather than inherently distinct oncogenic mechanisms between the two eras. Prospective matched-cohort studies are needed to disentangle the true oncogenic legacy of prior HCV infection from the confounding effects of background metabolic risk. This finding suggests that the residual HCC risk in the modern era is inextricably linked to the “second hit” of metabolic dysfunction.

Viral history as a “time accelerator”

The interaction between the HCV-induced “molecular memory” and ongoing metabolic stress is synergistic. Compared with MASLD patients without a history of HCV (“naïve” MASLD), post-SVR MASLD patients exhibited a markedly more aggressive disease trajectory. Prior viral infection appears to function as a “time accelerator”, advancing the biological age of the liver and compressing the timeline for metabolic carcinogenesis. As a result, phenomena such as fibrosis persistence and rapid HCC development, typically requiring decades to develop naïve MASLD, occur with accelerated kinetics in the post-SVR liver (72).

Risk stratification hierarchy

As summarized in Table 3, the data indicates a hierarchy of risk in which the combined phenotype of prior viral infection and current metabolic dysfunction sits at the apex. The presence of MASLD in post-SVR patients effectively doubles the hazard ratio for HCC, surpassing the risk associated with either condition in isolation.

Therapeutic implications and future directions

Elucidation of these four persistence mechanisms opens new avenues for chemoprevention in the post-SVR era. The current “watch and wait” surveillance strategy is insufficient for high-risk patients; targeted interventions against each molecular scar should be prioritized. Key considerations for each domain are outlined below.

• Epigenetic therapy: BET inhibitors (e.g., birabresib/OTX-015, GSK525762) targeting BRD4, and p300/CBP inhibitors, suppress oncogenic enhancers, including the SPHK1 and WNT10A loci, and revert H3K27ac marks in preclinical HCC models (23,24). Second-generation BET inhibitors are in phase I/II trials for solid tumors; none have been evaluated in the post-SVR chemoprevention context. [Evidence level: preclinical (in vitro/in vivo); no completed RCT in post-SVR chemoprevention].
• Metabolic modulation: statins represent the most evidence-supported chemopreventive strategy, with a meta-analysis of 10 propensity-score-matched studies (n=1,774,476) demonstrating a 48% reduction in HCC risk [hazard ratio (HR) 0.52; 95% confidence interval (CI): 0.37–0.72] (75); lipophilic statins show dose-dependent effects in HCV-specific cohorts (76). Metformin similarly reduced HCC risk by 51% in diabetic patients with chronic HCV [adjusted hazard ratio (aHR) 0.49] in a large propensity-matched Taiwanese cohort (77). Critically, all existing evidence derives from observational or retrospective data; no randomized controlled trial has yet specifically tested statins or metformin for post-SVR HCC chemoprevention (78). [Evidence level: Level 2–3 (retrospective cohort/meta-analysis); no completed RCT in post-SVR chemoprevention].
• Stromal normalization: simtuzumab, a monoclonal antibody targeting LOXL2, failed to reduce fibrosis in two large Phase 2b RCTs in NASH (F3–F4, n=477 over 96 weeks) (79) and in primary sclerosing cholangitis (80), attributed to irreversibility of collagen cross-links and compensatory cross-linking by other LOX isoforms. YAP/TAZ inhibitors (e.g., verteporfin) and small-molecule LOXL2 inhibitors (e.g., PXS-5153A) show preclinical anti-fibrotic efficacy but have not entered clinical trials for HCC prevention. [Evidence level: preclinical for YAP/TAZ inhibitors; phase 2b negative RCT for anti-LOXL2 approach].
• Metabolic normalization of MASLD-driven fibrosis: given that concurrent MASLD doubles HCC hazard ratio in post-SVR patients (see ‘The synergistic amplifier: metabolic dysfunction in the post-DAA era’; Table 3), FDA-approved metabolic dysfunction-associated steatohepatitis (MASH) therapies represent a mechanistically rational addition to the post-SVR chemopreventive armamentarium. Resmetirom (Rezdiffra™, THRβ agonist; approved March 2024) demonstrated in the phase 3 MAESTRO-NASH trial (n=966) MASH resolution in 25.9% versus 9.7% placebo (P<0.001) and fibrosis improvement by ≥1 stage in 24.2% versus 14.2% (P<0.001) (81). Its hepatoselective mechanism directly antagonizes the SREBP1c-driven DNL axis described in the metabolic reprogramming of this review, targeting the ‘metabolic scar’ at its transcriptional hub. Semaglutide 2.4 mg weekly (GLP-1R agonist) similarly achieved MASH resolution in 62.9% versus 34.3% placebo and fibrosis improvement in 36.8% versus 22.4% in the phase 3 ESSENCE trial (82,83), with additional evidence of GLP-1R-mediated suppression of macrophage NLRP3 inflammasome and NK cell metabolic restoration. Claudin-1 (CLDN-1) targeting via humanized monoclonal antibody offers a complementary anti-fibrotic strategy upstream of LOXL2: CLDN-1 drives TGF-β-mediated HSC activation through EGFR/ERK signaling, and anti-CLDN-1 mAb demonstrated anti-fibrotic efficacy in multiple non-HCV animal models (84). No trial has yet evaluated any of these agents specifically in the post-SVR chemoprevention setting. [Evidence level: Level 1 RCT data for resmetirom and semaglutide in MASH; preclinical for anti-CLDN-1; Level 5 extrapolation for post-SVR chemoprevention in all three].
• Differential HCC immunotherapy response by SVR status: a clinically important, and incompletely answered question is whether the ‘immunological scar’ described in the section on immunological scarring modifies the response to systemic immunotherapy when HCC does develop. Emerging data suggest that HCC etiology substantially influences the tumor immune microenvironment and therapeutic outcomes. Pfister et al. (Nature, 2021) demonstrated in murine models and human tissue that NASH-associated HCC harbors a distinct immunosuppressive microenvironment characterized by hepatic accumulation of CD8⁺ T cells with a tissue-damage (CXCR6⁺) rather than anti-tumor phenotype, providing a mechanistic explanation for reduced objective response rates to anti-PD-1 therapy in NASH/MASLD-HCC compared to viral-HCC (85). In contrast, HCV-related HCC, even arising post-SVR, is associated with higher tumor mutational burden (TMB) and a more inflamed baseline microenvironment. Exploratory analyses from the IMbrave150 trial and the CheckMate 040 study suggest numerically higher objective response rates in HBV/HCV-related HCC versus NASH/MASLD-HCC etiological subgroups, though these were not pre-specified and require prospective validation in cohorts that explicitly discriminate post-SVR status from active HCV infection (86,87). Critically, the ‘dual scar’ patient, post-SVR with concurrent MASLD, may harbor an intermediate immune phenotype in which TOX-driven T cell exhaustion compounds NASH-associated metabolic immunosuppression, potentially conferring resistance to both anti-PD-1 monotherapy and combination immunotherapy. Dedicated studies stratified by HCV SVR status and concurrent MASLD are urgently needed. [Evidence level: Level 2 (exploratory subgroup analyses from phase 3 RCTs); no dedicated post-SVR-specific RCT evaluating immunotherapy response].

Although robust biomarker candidates, including the epigenetic ’scar signature’ (e.g., SPHK1 expression in PBMCs) and LOXL2, have been identified, they remain investigational. Translating these into a validated, non-invasive ‘molecular risk score’ and conducting rigorous chemoprevention trials in high-risk post-SVR populations are the two most urgent priorities to bridge the gap between molecular insight and clinical practice (77,88).

Strengths and limitations

This review has several notable strengths. First, it synthesizes four mechanistically distinct yet interconnected oncogenic pillars, epigenetic, metabolic, immunological, and stromal, into a unified framework, providing a more comprehensive account of post-SVR hepatocarcinogenesis than single-pathway reviews. Second, mechanistic claims are explicitly graded by evidence level throughout, and the limitations of key foundational studies (e.g., the single-center origin of the H3K27ac ChIP-seq data) are acknowledged inline, enhancing transparency. Third, the review incorporates the most recent literature (up to December 2025) on the MASLD-HCV interaction, a rapidly evolving and clinically relevant axis. Fourth, the synthesis of biomarker candidates alongside therapeutic targets provides a translational roadmap directly aligned with the core principles of translational medicine.

Several limitations must be acknowledged. First, the proposed mechanistic framework relies largely on correlative data from observational studies and animal models; direct causal evidence and the true irreversibility of molecular “scars” in humans require prospective longitudinal validation. Second, substantial patient heterogeneity exists, and the unified model may oversimplify complex interactions between viral sequelae and concurrent metabolic dysfunction, which vary significantly by fibrosis stage and disease duration. Third, the suggested therapeutic interventions (e.g., targeting BRD4, LOXL2) remain preclinical and lack validation from randomized controlled trials regarding clinical safety and efficacy. Fourth, epigenetic data derive predominantly from a single landmark study (7); independent multi-center replication in ethnically diverse cohorts is required before these findings can be considered robust. Finally, the predominance of data from HCV genotype 1 and Western cohorts may limit generalizability to other viral genotypes and global populations, including Southeast Asian cohorts in whom genotypes 3 and 6 are prevalent.

Conclusions

The eradication of HCV with DAAs represents a monumental medical achievement, yet it has unveiled a complex biological reality in which the liver may retain durable molecular alterations attributable to the infection, the reversibility of which under therapeutic conditions remains an active area of investigation. This review has delineated the deep mechanisms of this memory, including epigenetic H3K27ac scarring, metabolic SPHK1/SREBP rewiring, immunological TOX-driven exhaustion, and stromal LOXL2-mediated stiffness.

These findings underscore that SVR is a milestone, not a finish line. The persistence of these oncogenic drivers, particularly in the presence of metabolic cofactors like obesity and diabetes, necessitates a paradigm shift in patient management. Future strategies must move beyond simple viral eradication toward achieving “molecular remission” through targeted therapies designed to attenuate or reverse the molecular sequelae of HCV, a concept that may ultimately redefine ‘cure’ in the post-DAA era. Accordingly, post-SVR patients, especially those with comorbid MASLD, warrant intensified liver surveillance compared with the general population. Furthermore, urgent research is needed to identify clinically applicable biomarkers capable of monitoring this carcinogenic trajectory, ultimately enabling the effective elimination of liver cancer risk.

Acknowledgments

The authors gratefully acknowledge the staff of the Center of Excellence in Clinical Virology and the International Program in Medical Sciences, Faculty of Medicine, Chulalongkorn University, for their support throughout this study. All figures (Figures 1-3) were created with BioRender (BioRender.com) under an institutional academic publication license (Agreement Nos. BW29MTWJBD, CD29MTVY9N, and ZC29MTWS8M). We hereby declare that generative AI (Gemini Advanced, Google LLC) was employed solely for the refinement of the English language, proofreading, and enhancement of readability within this manuscript. All content, concepts, data analysis, interpretations, and scientific findings were wholly conceived and developed by the authors. Following the language editing process, the authors conducted a thorough review of the final version to ensure its accuracy, integrity, and adherence to academic standards.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0031/rc

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0031/prf

Funding: This study was supported by the “Graduate Scholarship Program for ASEAN or Non-ASEAN countries” by Chulalongkorn University; the MK Restaurant Group Aunt Thongkum Foundation; the BJC Big C Foundation; the Center of Excellence in Clinical Virology, Chulalongkorn University; the King Chulalongkorn Memorial Hospital; and the Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University (No. RA-MF-28/69).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0031/coif). D.H.H.L. reports support from the “Graduate Scholarship Program for ASEAN or Non-ASEAN countries” by Chulalongkorn University. Y.P. reports grant support from the MK restaurant Group Aunt Thongkum Foundation, BJC Big C Foundation, Center of Excellence in Clinical Virology, King Chulalongkorn Memorial Hospital, and the Ratchadapiseksompotch Fund (No. RA-MF-28/69). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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