Metabolic dysfunction-associated steatotic liver disease and the consequence of extra-hepatic malignancy

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver condition worldwide, affecting an estimated one-quarter to one-third of the global adult population. Once conceptualized primarily as a hepatic disorder, MASLD is now recognized as a systemic metabolic disease with broad extra-hepatic consequences. Among the most clinically significant of these is a rising body of evidence linking MASLD to an increased risk of malignancies outside the liver. This review synthesizes current evidence on extra-hepatic cancers in MASLD, organized into two categories: Gastrointestinal (GI)-related malignancies and non-GI malignancies. We discuss the shared oncogenic mechanisms underlying these associations, including insulin resistance, chronic inflammation, lipotoxicity, gut microbiome dysbiosis, and adipokine dysregulation. Emerging data demonstrates rising trends in extra-hepatic cancer burden in MASLD populations, with particular concern for young-onset disease and advanced hepatic fibrosis as risk-amplifying factors. We also address current diagnostic gaps and the clinical imperative for developing MASLD-specific cancer surveillance strategies.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Extra-hepatic malignancy; Colorectal cancer; Pancreatic cancer; Breast cancer; Insulin resistance; Obesity; Cancer surveillance; Gut microbiome; Inflammation

Core Tip: Metabolic dysfunction-associated steatotic liver disease (MASLD) confers increased risk of extra-hepatic malignancies spanning multiple organ systems, beyond its well-recognized association with hepatocellular carcinoma. Shared oncogenic pathways which include insulin resistance, chronic systemic inflammation, lipotoxicity, and gut dysbiosis, link MASLD to both gastrointestinal (GI) cancers (colorectal, pancreatic, esophagogastric, biliary) and non-GI cancers (breast, gynecologic, thyroid, urinary, lung). Globally, the burden and prevalence of MASLD is rising, with young-onset disease and advanced fibrosis as key risk amplifiers. Dedicated cancer surveillance protocols for MASLD populations are urgently needed.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the most common chronic liver condition globally[1,2]. It is defined by the presence of hepatic steatosis with at least one trait of metabolic syndrome in the absence of significant alcohol consumption or other identifiable causes of hepatic steatosis. Initially the disease was described as non-alcoholic fatty liver disease (NAFLD) with nomenclature shifting toward the name metabolic associated fatty liver disease (MAFLD) as prevalence and research proved its systemic complexity[1]. In 2023, the multisociety Delphi consensus concluded a definition of MASLD to provide a non-stigmatizing and accurate representation of the disease[2]. Worldwide the prevalence of MASLD continues to rise with a prevalence of approximately 25%-38% driven by parallel obesity and type 2 diabetes epidemics[3]. There are notable geographic discrepancies, however it remains evident the overall healthcare burden is substantial[4]. MASLD is not a disease restricted to hepatic manifestations; rather clinical evidence continues to show its systemic effect. Cardiovascular disease (CVD), chronic kidney disease, type 2 diabetes mellitus (T2DM), and colorectal cancers are the most significant complications of MASLD and causes for patient mortality[5]. Important liver physiological mechanisms are impacted in MASLD believed to be associated with “systemic inflammatory milieu initiated partly by liver-secreted cytokines and molecules”[6]. Consequently, this inflammatory state likely contributes toward systemic insulin resistance and related metabolic dysfunction which play a pathogenic role in development of liver-related morbidities and extrahepatic complications[7]. The leading cause of death is predominantly CVD followed by malignancies, liver-related mortality, and diabetes-related mortality[8]. Extrahepatic malignancy related deaths have outpaced those from hepatocellular carcinoma (HCC) and given the rapidly increasing MASLD population burden this poses a critical health and economic issue[9]. The 2022 meta-analysis completed by Thomas et al[10] demonstrated a pooled extrahepatic cancer incidence rate in MASLD was 10.58 per 1000 person-years, over eight-fold more frequent than HCC. Additional studies confirm this rising trend and identify that the malignancy burden applies across multiple organ systems including gastrointestinal (GI), pulmonary, breast, gynecological, and urinary[11,12]. Although CVD remains the leading cause-specific mortality in patients with MASLD, malignancies consistently represent the second leading cause of death, frequently outpacing liver-related mortality[13,14]. This review provides a comprehensive synthesis of the current evidence linking MASLD to extra-hepatic malignancies, organized according to a dual framework: GI-related cancers and non-GI cancers. For each cancer type, we examine epidemiological associations, proposed oncogenic mechanisms, and emerging trends. We also discuss the broader implications for cancer surveillance and risk reduction in MASLD populations. While several narrative reviews have addressed individual MASLD-cancer associations, the present synthesis integrates GI and non-GI malignancies within a mechanistic framework while explicitly incorporating young-onset disease, fibrosis-stage stratification, sex-specific dimorphism, and their surveillance implications, which we frame as a research and practice agenda rather than a claim of comprehensiveness.

MASLD PATHOPHYSIOLOGY AND ONCOGENESIS: SHARED MECHANISMS

Before examining individual cancer types, it is essential to establish the mechanistic framework connecting MASLD to extra-hepatic malignancy. Several interrelated pathophysiological pathways common to MASLD create a systemic pro-oncogenic milieu predisposing to cancer development across multiple organ systems.

Insulin resistance and hyperinsulinemia

Evidence suggests that insulin resistance and increased insulin levels are key hormonal mechanisms linked to elevated risk of several cancer types[15]. In patients with MASLD there is a notable predisposition for developing T2DM[16]. Hyperinsulinemia is thought to promote oncogenesis through upregulation of insulin-like growth factor-1 (IGF-1) and subsequent activation of intracellular signaling pathways involved in mitogenesis, inhibition of apoptosis, and angiogenesis[15]. Insulin resistance therefore represents a central driver of both MASLD progression and carcinogenesis.

Chronic low-grade inflammation and cytokine milieu

Chronic low-grade inflammation is a defining biological feature of MASLD and a highly suspected mediator of its extrahepatic oncogenic burden. In a pro-inflammatory state, oncogenic mechanisms are constitutively activated. Targher and colleagues argue that this chronic inflammatory state is “crucially involved in MASLD progression” and additionally promotes extrahepatic cancers, with nuclear factor kappaB (NF-κB) centrally implicated in the generation of hepatic insulin resistance[7]. There is evidence that fat deposition induces dynamic changes fostering inflammation and immune responses that enhance cancer susceptibility[17]. With obesity coexisting in 80%-90% of patients with MASLD, the so-called “metainflammation” of adipose tissue compounds the hepatic inflammatory signal, producing a sustained systemic milieu of elevated tumor necrosis factor alpha, interleukin-6, high-sensitivity C-reactive protein, and interleukin-1RA[7]. Direct quantitative support for this pathway has recently emerged from a United Kingdom Biobank analysis in which 11.2%-31.0% of MASLD-cancer was mediated by inflammation[18].

Lipotoxicity and oxidative stress

In MASLD, hepatic accumulation of saturated free fatty acids (FFAs) and their lipotoxic intermediates, including diacylglycerols, ceramides, and lysophosphatidylcholine, exceeds the buffering capacity of mitochondrial β-oxidation. This drives a cascade of injurious intracellular events with oncogenic consequences. The resulting mitochondrial structural and functional dysfunction is central to this process: Impaired electron transport chain activity generates excess reactive oxygen species (ROS), which in turn inflict oxidative damage to DNA, proteins, and membrane lipids[19]. Lipid peroxidation byproducts, most notably malondialdehyde and 4-hydroxynonenal, form mutagenic DNA adducts, induce strand breaks, and promote epigenetic dysregulation including aberrant CpG island methylation that silences tumor suppressor genes[19]. Mitochondrial dysfunction further disrupts cellular bioenergetics and amplifies the pro-inflammatory signaling initiated by upstream insulin resistance, creating a self-reinforcing cycle of lipotoxic and oxidative injury[19]. In the broader metabolic context of altered lipid substrate utilization and FFA signaling, impaired ketogenic flux, which normally acts as a mitochondria-protective pathway, further illustrates how dysregulated lipid metabolism in MASLD generates systemic oncogenic pressure beyond the liver[20].

Gut microbiome dysbiosis and the gut-liver axis

MASLD is both a cause and consequence of gut microbiome dysbiosis, and the bidirectional gut-liver axis represents one of the most mechanistically detailed pathways linking MASLD to extrahepatic malignancy. In healthy physiology, the intestinal microbiota generate short-chain fatty acids (SCFAs), principally butyrate, propionate, and acetate, through fermentation of dietary fiber[21]. These metabolites exert anti-inflammatory, barrier-protective, and regulatory T-cell-inducing effects on the colonic mucosa[21]. In MASLD-associated dysbiosis, SCFA-producing taxa (principally Faecalibacterium prausnitzii and Roseburia spp.) are depleted and replaced by dysbiotic, gram-negative organisms, shifting the hepatic portal influx toward lipopolysaccharide and other pathogen-associated molecular patterns that activate hepatic toll-like receptor-4 and NF-κB signaling, sustaining the systemic inflammatory milieu described in the subsection on chronic low-grade inflammation and cytokine milieu[5,22].

Simultaneously, dysbiotic microbiota alter the conversion of primary to secondary bile acids: Reduced 7α-dehydroxylation activity by Clostridium cluster XIVa and IV species depresses the ratio of primary-to-secondary bile acids, elevating deoxycholic acid (DCA) and lithocholic acid concentrations in the enterohepatic and systemic circulation[21]. These secondary bile acids are genotoxic and pro-proliferative at concentrations found in the colon, biliary tree, and liver, and experimental blockade of DCA production suppresses hepatic carcinogenesis in murine models[5]. Beyond bile acid metabolism, dysbiosis-associated increases in intestinal permeability allow microbial translocation products to reach distant organs via the systemic circulation, a mechanism relevant to extrahepatic carcinogenesis at multiple sites[22,23]. Collectively, the gut-liver axis serves as a shared mechanistic conduit for MASLD-associated oncogenesis, most prominently within the GI tract (Figure 1). This provides a biological rationale for the especially robust MASLD-colorectal cancer (CRC) associations described in the discussion of colorectal cancer.

Figure 1 Shared oncogenic mechanisms of metabolic dysfunction-associated steatotic liver disease and extrahepatic malignancy as the downstream outcome. Metabolic dysfunction-associated steatotic liver disease and its shared oncogenic mechanisms, which include insulin resistance, chronic inflammation, lipotoxicity, gut-liver axis dysbiosis, extracellular vesicle signaling, adipose and hormonal dysregulation, and fibrosis severity, predispose to gastrointestinal and non-gastrointestinal extrahepatic malignancies. IGF-1: Insulin-like growth factor 1; NF-κB: Nuclear factor kappa B; STAT3: Signal transducer and activator of transcription 3; ROS: Reactive oxygen species; GI: Gastrointestinal; MASLD: Metabolic dysfunction-associated steatotic liver disease.

Hepatocyte-derived extracellular vesicles and systemic crosstalk

Beyond the traditional pathways of cytokine signaling and metabolite exchange, hepatocyte-derived extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as a distinct mechanism of inter-organ communication relevant to MASLD-associated extrahepatic oncogenesis. Steatotic and stressed hepatocytes release EVs whose composition reflects the altered lipidomic, transcriptomic, and proteomic state of the injured liver. These vesicles transport bioactive cargo, including microRNAs, mRNAs, lipid mediators, and damage-associated molecular patterns, through the systemic circulation to distant tissues, where they modulate recipient cell phenotype and function[24]. In MASLD, this EV-mediated signaling contributes to progression of hepatic injury but also extends the pathophysiology of the disease beyond the liver, providing a candidate mechanism by which a “local” hepatic disorder produces “global” oncogenic effects in distant organs such as the breast, lung, and colon[23,24]. The broader framework of inter-organ crosstalk linking MAFLD to multi-organ disease, mediated by insulin resistance, visceral adiposity, and now EV signaling, reinforces this conceptual shift from viewing MASLD as a hepatic condition to viewing it as a systemic metabolic disorder with measurable downstream oncologic consequences[23].

Adipose tissue and hormonal dysregulation

MASLD exists within a broader context of metabolic-endocrine dysregulation in which adipose tissue is a major contributor to systemic oncogenic signaling. The disease has been reciprocally linked to multiple endocrinopathies, including hypothyroidism, polycystic ovary syndrome, growth hormone deficiency, hypogonadism, and hypercortisolism, each of which can independently modify cancer risk[25]. MASLD is now increasingly understood as a sexually dimorphic disease where circulating estrogen and androgen levels, and the estrogen-to-androgen ratio, influence hepatic disease trajectory and the spectrum of associated hormone-sensitive cancers, particularly breast and gynecologic malignancies[26].

Multiple mechanisms originating from adipose tissue are thought to mediate this hormonal contribution to cancer risk. Adipose tissue is a principal site of aromatase activity, and peripheral aromatization of androgens to estrogens generates an estrogen excess that, when unopposed by progesterone, sustains proliferative signaling in estrogen-receptor-positive breast and endometrial tissue[26]. Adipokine balance also becomes disturbed. Leptin, which rises in the setting of MASLD and obesity, activates JAK/STAT, MAPK, and PI3K/Akt pathways implicated in tumor proliferation and angiogenesis, while adiponectin, an anti-proliferative and insulin-sensitizing adipokine, is paradoxically reduced[26]. In addition, dysregulation of hepatokines in MASLD including fetuin-A, fibroblast growth factor 21, and selenoprotein P, further contributes to peripheral inflammation and altered tissue homeostasis with downstream oncologic implications[26]. Together, these endocrine and adipokine disturbances offer an explanation for the disproportionate burden of breast, endometrial, and ovarian cancer observed in women with MASLD, as detailed in the discussions of breast cancer, gynecologic cancers, and sex differences and dimorphic cancer risk.

Fibrosis severity as a cancer risk modifier

While hepatic fibrosis is the dominant determinant of liver-related mortality in MASLD, its relationship with extrahepatic cancer risk is more nuanced. The Vilar-Gomez et al[27] multinational cohort of 458 patients with biopsy-confirmed advanced NAFLD demonstrated a critical clinical distinction: Patients with bridging fibrosis (F3) developed predominantly nonhepatic cancers and vascular events, whereas those with cirrhosis (F4) developed predominantly liver-related events. This finding identifies advanced non-cirrhotic fibrosis as the key clinical stage at which extrahepatic oncologic risk is concentrated. The NASH Clinical Research Network prospective study by Sanyal et al[28] confirmed fibrosis stage as the dominant predictor of all-cause mortality, with patients harboring advanced fibrosis at baseline experiencing markedly elevated cumulative mortality over a median 4-year follow-up. Simon et al[29], in a Swedish population-based cohort of 8892 adults with biopsy-confirmed NAFLD, demonstrated that overall cancer incidence rose monotonically across categories of simple steatosis, non-fibrotic NASH, non-cirrhotic fibrosis, and cirrhosis, with diabetes further amplifying this gradient. However, the dose-response was driven primarily by HCC and only modestly by extrahepatic cancers (pancreatic, kidney/bladder, and melanoma). Importantly, the Swedish Björkström et al[30] cohort study reported that liver cancer risk in NAFLD was elevated independent of cirrhosis, and that the extrahepatic cancer signal, though slightly elevated, was modest in magnitude. Similarly, the Thomas 2022 meta-analysis found that extrahepatic cancer incidence was not further amplified in patients with advanced fibrosis or cirrhosis[10]. These findings are consistent with a model in which extrahepatic carcinogenesis in MASLD is driven by systemic metabolic exposure rather than the hepatic fibrosis pathway itself. In addition, a multicenter cross-sectional study of the Chinese MASLD population found that cardiometabolic burden, including hypertension and hyperglycemia, together with higher Fibrosis-4 index (FIB-4), was associated with extrahepatic cancers. This indicated that metabolic exposure and fibrosis stage are jointly related to extrahepatic risk[31]. Genetic data further support a systemic rather than a liver-specific driver in a meta-analysis of 232033 individuals with MASLD which found that the PNPLA3 I148M variant conferred dose-dependent increases in liver-related events and HCC but showed no association with extrahepatic cancers among homozygous risk-allele carriers compared with wild-type homozygotes [hazard ratio (HR) 0.96, 95%CI: 0.67-1.37], implying that the extrahepatic cancer excess in MASLD is mediated by shared metabolic dysfunction rather than by the hepatic genetic risk allele[32]. Collectively, these data support the use of fibrosis stage as a clinical stratifier for liver-related outcomes, while extrahepatic cancer risk in MASLD is best understood as dependent on cumulative metabolic burden and disease duration rather than fibrosis stage alone.

GASTROINTESTINAL EXTRAHEPATIC MALIGNANCIES IN MASLD

The GI tract shares key anatomical and physiological connections with the liver through the portal circulation and gut-liver axis, which may partly explain the particularly strong associations between MASLD and GI tract malignancies. The key features of GI-related extra-hepatic cancers in MASLD are summarized in Table 1.

Table 1 Gastrointestinal extrahepatic malignancies in metabolic dysfunction-associated steatotic liver disease: Cancer type, key studies, risk estimates, proposed mechanisms, and trends.

Cancer type	Ref.	Risk estimate (HR or OR)	Proposed mechanisms	Trend/notes
Colorectal cancer	Wu et al[33], 2026 (international Delphi consensus, Gut); Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis, n ≈ 16.7M); Allen et al[35], 2019 (community cohort, J Hepatol); Azimi et al[34], 2025 (meta-analysis, n > 56M)	HR 1.33 (Zhou et al[37] meta-analysis); approximately 1.5-2-fold (Mantovani et al[12], 2022); OR 1.37 (Azimi et al[34], 2025)	Gut dysbiosis; secondary bile acid alterations; hyperinsulinemia; mucosal inflammation; IGF-1 axis activation	Rising; strongest GI cancer association; independent of obesity and T2DM
Pancreatic cancer	Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis, Eur J Clin Invest); Thomas et al[9], 2024 (review, Lancet GE&H); Thomas et al[10], 2022 (meta-analysis, Eur J Cancer); Mantovani et al[36], 2024	HR 1.41 (Zhou et al[37] meta-analysis); approximately 1.5-2-fold (Mantovani et al[12], 2022)	Insulin resistance; visceral adiposity; acinar inflammation; shared T2DM pathway	Rising; evidence strengthening with larger population cohorts
Esophageal/gastric cancer	Zou et al[40], 2023 (meta-analysis); Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis); Thomas et al[9], 2024 (Lancet GE & H); Mantovani et al[36], 2024	Gastric: HR 1.47 (Zhou et al[37]), RR 1.49 (Zou et al[40]); esophageal: RR 1.76 (Zou et al[40]), null in Zhou et al[37] meta-analysis	GERD; Barrett’s esophagus; visceral adiposity; reflux-related mucosal injury	Moderate; gastric cancer signal more consistent than esophageal across meta-analyses
Biliary tract cancer (gallbladder/cholangiocarcinoma)	Park et al[41], 2021 (nationwide Korean cohort, n ≈ 8.1M, Eur J Cancer); Zhou et al[37], 2024 (meta-analysis); Mantovani et al[36], 2024	BTC overall: AHR 1.28 (Park et al[41], 2021), HR 1.27 (Zhou et al[37]); cholangiocarcinoma aHR 1.33; gallbladder aHR 1.14	Biliary stasis; cholelithiasis; chronic biliary inflammation	Emerging; cholangiocarcinoma shows the stronger signal; gallbladder signal weaker; Western validation limited

HR: Hazard ratio; OR: Odds ratio; aHR: Adjusted hazard ratio; RR: Relative risk; IGF-1: Insulin-like growth factor-1; T2DM: Type 2 diabetes mellitus; GERD: Gastroesophageal reflux disease; BTC: Biliary tract cancer; GI: Gastrointestinal.

CRC

The association between CRC and MASLD is the most extensively characterized of the GI extrahepatic malignancies. The 2026 international Delphi consensus statement affirmed that MASLD independently increases CRC risk and that greater metabolic burden and disease severity amplify this risk[33]. An updated 2025 meta-analysis of 48 studies encompassing more than 56 million participants reported pooled odds ratios of 1.37 for CRC, 1.81 for colorectal adenomas, and 1.86 for colorectal polyps among individuals with NAFLD/MASLD[34]. A meta-analysis by Mantovani et al[12] similarly described an approximately 1.5- to 2-fold elevation in CRC risk, and a 21-year community-based cohort demonstrated a near 2-fold increase in incident malignancies, with GI tumors among the predominant sites[12,35].

The mechanistic basis is best framed through the gut-liver axis. MASLD-associated intestinal dysbiosis alters microbial conversion of primary to secondary bile acids, particularly DCA, which has been implicated in colonic genotoxicity and tumor promotion. Concurrent depletion of SCFA-producing taxa attenuates mucosal anti-inflammatory and regulatory T-cell signaling[21,22]. Increased intestinal permeability and lipopolysaccharide translocation drive NF-κB-mediated chronic low-grade inflammation, while systemic hyperinsulinemia and IGF-1 axis activation provide additional mitogenic stimuli along the adenoma-carcinoma sequence[36].

Importantly, the MASLD-CRC association persists after adjustment for obesity, T2DM, and other components of metabolic syndrome, supporting an independent oncogenic contribution from hepatic steatosis and hepatic fibrosis itself[12,36]. This association extends to lean MASLD, where the magnitude of the link with colorectal adenoma may exceed that observed in obese individuals[34]. Such findings underscore the need for MASLD-specific CRC risk stratification tools beyond conventional metabolic markers.

Pancreatic cancer

Pancreatic ductal adenocarcinoma represents a biologically plausible target of MASLD-driven metabolic stress. The available epidemiological data support a positive, though more modest, association than observed for CRC. In the largest meta-analysis on this question, encompassing 18 cohort studies and approximately 16.7 million participants, MASLD was associated with a pooled hazard ratio of 1.41 (95%CI: 1.11-1.79) for incident pancreatic cancer[37]. The Mantovani et al[12] meta-analysis in Gut (10 cohorts, 182202 participants) similarly demonstrated a 1.5- to 2-fold increase in GI cancer risk, including pancreatic cancer, among individuals with NAFLD, with effect estimates persisting after adjustment for age, sex, smoking, obesity, and diabetes. The pooled-incidence meta-analysis by Thomas et al[10] further reinforced pancreatic cancer as one of the malignancies with elevated incidence in NAFLD. Notably, in that analysis extrahepatic cancer incidence was not further amplified in patients with advanced fibrosis or cirrhosis. This pattern highlights the importance of systemic metabolic, rather than purely fibrosis-driven mechanisms, in pathways of pancreatic carcinogenesis. Earlier systematic reviews and contemporary narrative syntheses have reached convergent conclusions[9,11,36].

Mechanistically, MASLD and pancreatic cancer share several oncogenic axes. Hepatic insulin resistance with compensatory hyperinsulinemia activates insulin/IGF-1 signaling, exerting mitogenic, anti-apoptotic, and pro-angiogenic effects on pancreatic acinar and ductal epithelium[15]. Visceral adiposity and ectopic intra-pancreatic fat deposition generate a local pro-inflammatory milieu, with adipokine dysregulation, FFA lipotoxicity, and macrophage-mediated stromal remodeling implicated in acinar-to-ductal metaplasia, a recognized precursor lesion[16,36]. T2DM, which develops in a substantial proportion of MASLD patients, is itself an established pancreatic cancer risk factor and likely functions as both co-driver and effect modifier. This overlap is acknowledged in the 2026 American Diabetes Association (ADA) Standards of Care and the 2025 ADA-Endocrine Society consensus, both of which cite GI cancers, including pancreatic cancer, among the extrahepatic manifestations of MASLD warranting integrated cardiometabolic-oncologic risk assessment[38,39].

Overall, the MASLD-pancreatic cancer signal is consistent across independent meta-analyses but of moderate magnitude and disentangling MASLD’s contribution from that of T2DM and central adiposity remains a methodological challenge. Dedicated cohorts with detailed adjustment for diabetes status, glycemic control, and pancreatic imaging are needed to refine risk estimates and inform any future surveillance strategy.

Esophageal and gastric cancer

The association between MASLD and upper GI malignancies is biologically plausible, mediated through visceral adiposity, gastroesophageal reflux disease (GERD), Barrett’s esophagus, and shared metabolic-inflammatory pathways. However, the supporting epidemiological data are less consistent than for CRC. The most directly relevant evidence comes from the systematic review and meta-analysis by Zou et al[40], which pooled data from 8 studies encompassing 8629525 participants and reported significantly increased risks of both gastric cancer [pooled relative risk (RR) 1.49, 95%CI: 1.17-1.91] and esophageal cancer (pooled RR 1.76, 95%CI: 1.34-2.32) among patients with MAFLD/NAFLD. The Mantovani et al[12] meta-analysis in Gut similarly grouped esophageal and gastric cancers within the GI cancers showing a 1.5- to 2-fold increase in MASLD, with risk independent of the major confounders. Importantly, however, the larger Zhou et al[37] meta-analysis of 18 cohort studies (approximately 16.7 million participants) found a positive signal for gastric cancer (HR 1.47, 95%CI: 1.07-2.01) but a null association for esophageal cancer (HR 1.26, 95%CI: 0.86-1.86). This indicates that, while pooled cohort data support a gastric cancer signal, they do not consistently reproduce the esophageal cancer association observed in earlier studies. The Thomas et al[9] review and Mantovani et al[36] GI-cancers narrative highlight the same heterogeneity and call for site- and histology-specific stratification.

The proposed mechanisms differ between the two sites. For esophageal adenocarcinoma, central adiposity associated with MASLD promotes GERD and Barrett's esophagus, providing a chronic inflammatory and metaplastic substrate for malignant transformation[9,36]. For gastric cancer, hyperinsulinemia, IGF-1 axis activation, and adipokine dysregulation overlap with mechanisms implicated in colorectal carcinogenesis, while gut-liver axis perturbations may further modulate gastric mucosal homeostasis[36].

The gastric cancer signal in MASLD appears more reproducible than the esophageal cancer signal, with the latter being driven primarily by Zou et al[40] and not confirmed in the larger and more recent Zhou et al[37] pooled analysis. Histology-stratified analyses (esophageal adenocarcinoma vs squamous cell carcinoma; gastric cardia vs non-cardia) and adjustment for Helicobacter pylori status, smoking, and alcohol exposure are needed to clarify the magnitude and biological direction of these associations.

Biliary tract cancers (gallbladder and cholangiocarcinoma)

Biliary tract cancers (BTCs) represent an emerging and biologically coherent association with MASLD, mechanistically linked through chronic biliary stasis, cholelithiasis, and low-grade inflammatory injury to the biliary epithelium. The most informative single dataset is the nationwide South Korean cohort study by Park et al[41], which followed 8120674 adults and reported a significantly increased risk of BTC overall in NAFLD [(adjusted hazard ratio, aHR) 1.28, 95%CI: 1.20-1.37], with the strongest signal for cholangiocarcinoma (aHR 1.33, 95%CI: 1.23-1.43) and a more modest, borderline-significant signal for gallbladder cancer (aHR 1.14, 95%CI: 1.003-1.29); concomitant NAFLD and diabetes were associated with a 47% increase in BTC risk. This nationwide signal is reinforced by the Zhou et al[37] meta-analysis of 18 cohort studies (approximately 16.7 million participants), which reported a pooled HR of 1.27 (95%CI: 1.18-1.37) for BTC in MASLD. The Mantovani et al[36] narrative review on GI extrahepatic cancers in MASLD frames these findings within a coherent mechanistic and epidemiologic synthesis.

Mechanistically, MASLD is associated with cholesterol gallstone disease, biliary sludge, and altered bile composition, all of which promote chronic biliary inflammation and a pro-carcinogenic ductal microenvironment. Hepatic insulin resistance and dyslipidemia drive supersaturation of bile with cholesterol, while gut-liver axis perturbations and altered enterohepatic bile acid cycling, particularly elevated secondary bile acids such as DCA, provide additional genotoxic and proliferative stimuli to cholangiocytes[36]. T2DM, which commonly coexists with MASLD[38,39], independently amplifies BTC risk and likely accounts for some of the diabetes-MASLD synergy observed in Park et al[41].

A few caveats are worth noting. The cholangiocarcinoma signal is consistently stronger than the gallbladder cancer signal, which contrasts with the broader obesity-cancer literature, where gallbladder cancer is the more commonly reported biliary association. Whether this reflects true biology or differential ascertainment requires further study. A further limitation is that much of the strongest evidence derives from a single Asian nationwide cohort. Validation in Western populations, particularly with differentiation into intrahepatic and extrahepatic cholangiocarcinoma, remains limited. Despite these caveats, BTC, and particularly cholangiocarcinoma, is an emerging MASLD-associated malignancy warranting attention in long-term cancer surveillance discussions.

NON-GASTROINTESTINAL EXTRAHEPATIC MALIGNANCIES IN MASLD

Beyond the GI tract, MASLD has become increasingly associated with malignancies in other organ systems through systemic hormonal, inflammatory, and metabolic mechanisms. Key features of the non-GI extrahepatic malignancies are briefly summarized in Table 2.

Table 2 Non-gastrointestinal extrahepatic malignancies in metabolic dysfunction-associated steatotic liver disease: Cancer type, key studies, risk estimates, proposed mechanisms, and trends.

Cancer type	Ref.	Risk estimate (HR or OR)	Proposed mechanisms	Trend/notes
Breast cancer	Lee et al[51], 2026 (nationwide Korean cohort); Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis); Thomas et al[9], 2024 (Lancet GE & H); Zhang and Nguyen[26], 2025 (review)	HR 1.17 (Zhou et al[37] meta-analysis); HR 1.20 in postmenopausal women with BMI 25-30 (Lee et al[51], 2026); OR approximately 1.2-1.5 (Mantovani et al[12], 2022)	Peripheral estrogen excess; leptin signaling; IR-IGF-1 axis; adipokine dysregulation	Rising; highest-burden non-GI cancer association; postmenopausal women at greatest risk
Endometrial cancer	Allen et al[35], 2019 (community cohort, J Hepatol); Mantovani et al[12], 2022 (meta-analysis, Gut); Thomas et al[10], 2022 (meta-analysis, Eur J Cancer); Thomas et al[9], 2024 (Lancet GE & H); Zhang and Nguyen[26], 2025 (review)	Approximately 2-fold uterine cancer risk in NAFLD (Allen et al[35], 2019); pooled OR approximately 1.5-2.1 across studies	Unopposed estrogen stimulation; hyperinsulinemia; adipokine excess	Rising; strong mechanistic plausibility; consistent across populations
Ovarian cancer	Park et al[46], 2025 (nationwide Korean cohort, n = 2.3M women, ages 20-39); Zhou et al[37], 2024 (meta-analysis); Zhang and Nguyen[26], 2025 (review, Metabolism)	HR 1.30 young-onset ovarian cancer (Park et al[46], 2025); HR 1.36 female genital organ cancers (Zhou et al[37] meta-analysis)	Hormonal dysregulation; PCOS overlap; adipokine signaling	Emerging; young-onset data of concern; limited overall evidence base
Thyroid cancer	Moon et al[47], 2025 (Korean cohort, thyroid); Zhou et al[37], 2024 (meta-analysis); Chen et al[49], 2025 (meta-analysis); Kwon et al[48], 2024 (cohort); Liu et al[43], 2022 (metabolism)	HR 1.36 (Moon et al[47], 2025); HR 1.46 (Zhou et al[37] meta-analysis); HR 1.69 in women (Liu et al[43], 2022 United Kingdom Biobank)	Insulin resistance; TSH dysregulation; thyroid nodularity in MASLD	Emerging; predominantly Asian cohort data; Western validation needed
Urinary system cancer (renal cell/bladder)	Bril and Elbert[68], 2025 (review); Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis); Thomas et al[10], 2022; Thomas et al[9], 2024	HR 1.45 (Zhou et al[37] meta-analysis); OR approximately 1.2-1.5 (Mantovani et al[12], 2022); kidney/bladder cancers documented in pooled NAFLD incidence data	Adiposity-driven ROS; chronic renal inflammation; altered adipokine signaling	Underexplored; mechanistically plausible; dedicated studies lacking
Lung cancer	Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis); Pan et al[69], 2025 (review); Thomas et al[9], 2024 (Lancet GE & H)	OR approximately 1.2-1.5 (Mantovani et al[12], 2022); null association in Zhou et al[37], 2024 meta-analysis	Systemic inflammation; adipokine-mediated bronchial epithelial effects; shared metabolic exposures	Mixed; signal present in some cohorts but null in pooled analyses; smoking confounding remains a key concern
Prostate cancer	Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis); Thomas et al[10], 2022 (meta-analysis, Eur J Cancer); Thomas et al[9], 2024 (Lancet GE & H)	Conflicting; null in pooled meta-analyses (Mantovani et al[12], 2022; Zhou et al[37], 2024); inverse association reported in some Korean cohorts	Testosterone deficiency may reduce androgen-driven risk; complex hormonal interplay in MASLD/obesity	Uncertain; inverse/null in most studies; mechanism warrants further investigation

HR: Hazard ratio; OR: Odds ratio; IR: Insulin resistance; IGF-1: Insulin-like growth factor-1; BMI: Body mass index; TSH: Thyroid-stimulating hormone; PCOS: Polycystic ovarian syndrome; ROS: Reactive oxygen species; GI: Gastrointestinal; NAFLD: Non-alcoholic fatty liver disease; MASLD: Metabolic dysfunction-associated steatotic liver disease.

Breast cancer

Breast cancer is one of the highest-burden non-GI malignancy associations in MASLD. In fact, in a Korean cohort of 25947 subjects followed for a median of 7.5 years, MASLD was independently associated with breast cancer in females after adjusting for demographic and metabolic factors (HR 1.92; 95%CI: 1.15-3.20)[42]. The findings were corroborated at scale; a meta-analysis of 10 cohorts amassing 182202 individuals reported that MASLD conferred an approximately 1.2 to 1.5-fold increased risk of breast cancer, regardless of age, sex, smoking, diabetes, and obesity[12]. More recently, a larger meta-analysis of 18 cohort studies (about 16.7 million participants) confirmed a statistically significant association between MASLD and breast cancer (HR 1.17; 95%CI: 1.08-1.26)[37]. Zhang and Nguyen[26] in 2025 further characterized MASLD as a sexually dimorphic disease, stating that sex hormones, particularly the levels and ratios of circulating estrogens and androgens, play a huge central role in both the development of MASLD and its association with hormone-sensitive cancers. The hormonal and adipokine mechanisms underlying this association, with their net effect being a sex-specific pro-tumorigenic environment in breast tissue, are detailed in the subsection on adipose tissue and hormonal dysregulation[26]. The risk is dimorphic by menopausal status, with an elevated risk directed towards postmenopausal women with MASLD. This reflects a greater contribution of peripheral aromatization to circulating estrogen levels after ovarian senescence[26]. Data seen in the United Kingdom Biobank supports this claim, showing MASLD was positively associated with postmenopausal breast cancer[43].

Gynecologic cancers (endometrial and ovarian)

Amongst all gynecologic malignancies, it has been found that endometrial cancer demonstrates the most consistent and strongest association with MASLD. This correlation is grounded by a robust hormonal and metabolic rationale. Estrogen excess and unopposed endometrial stimulation, hallmarks of the metabolic setting in MASLD, are linked to endometrial cancer spanning multiple meta-analyses. The Mantovani et al[12] meta-analysis (2022) reported that MASLD was associated with approximately 1.2 to 1.5-fold increased risk of gynecological cancers, independent of potential confounders. Interestingly, a JAMA review by Tilg et al[44] cited pooled data that showed MASLD was associated with a higher risk of gynecological cancers (HR 1.62; 95%CI: 1.13-2.32). The Zhou et al[37] meta-analysis (2024) of 18 cohort studies confirmed an association with female reproductive cancers (HR 1.36; 95%CI: 1.11-1.66). Thomas et al[10] cited that the common occurring extrahepatic cancers in MASLD included uterine malignancy, and additionally the incidence rates were not higher in patients with advanced fibrosis or cirrhosis. This suggests that what drives the gynecological risk is the metabolic environment, rather than the liver disease severity. A large nationwide Korean cohort study of roughly 2 million women by Jeong et al[45] provided granular data which was stratified by menopausal status. In premenopausal women, MASLD was associated with increased risks of endometrial cancer (HR 1.63; 95%CI: 1.50-1.79) and ovarian cancer (HR 1.22; 95%CI: 1.12-1.33). Similarly, for postmenopausal women, MASLD conferred elevated risks for endometrial (HR 1.42; 95%CI: 1.32-1.54) and ovarian cancer (HR 1.14; 95%CI: 1.08-1.20).

Ovarian cancer has been less extensively studied in its association with MASLD. However, it has garnered attention after data from Park et al[46], who conducted a Korean cohort study of over 2 million women aged 20-39 years followed for a median of 11.5 years. Over a course of 27 million person-years of follow-up, 6319 women were diagnosed with young-onset ovarian cancer. MASLD was independently associated with an increased risk of young-onset ovarian cancer (HR 1.30; 95%CI: 1.16-1.45), and this risk increased with MASLD severity (moderate MASLD: HR 1.26; severe MASLD: HR 1.45, P for trend 0.01)[46]. Mechanistically, gynecological cancers share considerable overlap with breast cancer in the MASLD context, including estrogen excess, polycystic ovary syndrome-related anovulatory cycles, and dysregulated adipokine signaling[39].

Thyroid cancer

An emerging association between MASLD and thyroid cancer has been identified, with the most significant data shown from Asian cohort studies. In a cohort from Moon et al[47], analysis of roughly 200000 Korean adults aged ≥ 40 years found that MASLD was independently associated with a higher risk of thyroid cancer (HR 1.36; 95%CI: 1.17-1.58) over an average follow-up of 9.6 years, with metabolic and associated liver disease conferring a similar risk (HR 1.40; 95%CI: 1.04-1.88). In younger populations, Kwon et al[48] studied 1135967 participants aged 20-39 years and demonstrated a dose-response relationship. Compared with those with fatty liver index (FLI) of 30, individuals with an FLI between 30-60 had a significantly higher risk of thyroid cancer (men: HR 1.71; women: HR 1.81). Participants with higher cumulative FLI points and progression of MASLD over time exhibited incrementally higher thyroid cancer risk[48]. A meta-analysis by Chen et al[49], pooling eight cohort studies with roughly 19 million participants in total, confirmed that MASLD is linked to an increased risk of thyroid cancer (HR 1.46; 95%CI: 1.14-1.86), with the association particularly strong in the Chinese population (HR 2.24; 95%CI: 1.32-3.81) and among overweight individuals. The Zhou et al[37] meta-analysis (2024) reported a similar significant association (HR 1.46; 95%CI: 1.02-2.09). Wang et al[50] found that in a large Chinese male cohort, MASLD was associated with thyroid cancer (HR 2.79; 95%CI: 1.25-6.21), and this association increased with higher alanine aminotransferase levels. The proposed mechanisms center on insulin resistance and thyroid-stimulating hormone dysregulation, with thyroid nodularity potentially representing a shared endocrinopathy of the metabolic syndrome phenotype[25]. However, although the epidemiological signal is strengthening, further prospective studies are needed to clarify the degree and independence of this association across diverse populations.

Urinary system cancers (renal cell and bladder)

Urinary system cancers remain a relatively underexplored domain in the MASLD-malignancy literature. However, there is growing mechanistic plausibility and epidemiological support for associations with MASLD. The Zhou et al[37] meta-analysis (2024) reported a statistically significant association between MASLD and urinary malignancies (HR 1.45; 95%CI: 1.25-1.69), while a meta-analysis by Mantovani et al[12] found 1.2-1.5-fold increased risk. In a meta-analysis by Thomas et al[9], there was a significant effect of body mass index (BMI) on the association between MASLD and urinary system malignancies. This study suggested there may be an effect modifier of adiposity. Bu et al[18] from the UK Biobank confirmed a positive association between MASLD and kidney and bladder cancers over a median follow-up period of 13 years, and it was also noted that inflammation partially mediated the observed association by 11.2% to 31.0%. Liu et al[43] found that MASLD was significantly associated with kidney cancer (HR 1.77; 95%CI: 1.49-2.11) and bladder cancer (HR 1.26; 95%CI: 1.11-1.43), with kidney cancer remaining significant once adjusting for BMI, waist circumference, and metabolic syndrome. Adiposity-driven ROS generation, chronic renal inflammation, and altered adipokine signaling have all been proposed as candidate pathways linking MASLD to renal cell and bladder carcinogenesis[25,51]. Currently, the epidemiological evidence supports an association, but findings are heterogeneous across study populations, and dedicated mechanistic investigations are limited.

Lung cancer

Malignancy of the lung has been associated with MASLD in emerging biological and epidemiological data. The Mantovani et al[12] meta-analysis (2022) found that MASLD was associated with an increased risk of lung cancer, independent of confounders which included smoking. Thomas et al[9] reported that an umbrella meta-analysis also found a significantly increased risk of lung cancer in patients with MASLD. However, the more recent Zhou et al[37] meta-analysis of 18 cohort studies (2024) did not find a statistically significant association between lung cancer and MASLD (HR 1.01; 95%CI: 0.92-1.10), highlighting the heterogeneity in the current evidence base. Wang et al[50] found that MASLD was associated with lung cancer in a large Chinese male cohort (HR 1.23; 95%CI: 1.02-1.49), but this association was only seen in participants who smoked (HR 1.38; 95%CI: 1.03-1.84), suggesting that environmental exposures may confound the relationship. Bu et al[18], using United Kingdom Biobank data, demonstrated that inflammation partially mediates the MASLD-cancer association, providing a plausible biological link for lung cancer through systemic inflammation, adipokine-mediated alterations in bronchial epithelial biology, and environmental and metabolic exposures that affect pulmonary carcinogenesis. Further investigation to clarify confounding by smoking and other risk factors is needed.

Prostate cancer

The relationship between MASLD and prostate cancer has shown conflicting evidence. The Zhou et al[37] meta-analysis (2024) found no statistically significant association between MASLD and prostate cancer (HR 1.06; 95%CI: 0.94-1.19). Similarly, the Mantovani et al[12] meta-analysis did not demonstrate an independent association. Thomas et al[9] described that a meta-analysis with meta-regression showed a significant effect of BMI and pre-existing diabetes on the association between MASLD and prostate cancer, suggesting the relationship may be confounded or modified by these factors. Thomas et al[10] reported that prostate cancer was among the most frequently occurring extrahepatic cancers in MASLD by absolute incidence. However, the relative risk increase was modest and inconsistent across studies. Interestingly, a meta-analysis by Liu et al[11] reported a significant association between MASLD and prostate cancer, though the results have not been consistently replicated in larger, more recent meta-analyses. The mechanistic distinctions underlying these conflicting findings may correlate to androgen pathway complexities in the setting of MASLD. Testosterone deficiency, which is common in MASLD as well as obesity, may paradoxically attenuate androgen driven prostate carcinogenesis, thereby offsetting the pro-tumorigenic effects of insulin resistance and chronic inflammation[12]. This discordance underscores the need for a careful, critical appraisal and sex-specific mechanistic analysis when further evaluating cancer risk in the MASLD population.

TRENDS, DISEASE BURDEN, AND SPECIAL POPULATIONS

Overall trends in extrahepatic cancer risk in MASLD

The cumulative evidence linking MASLD to extrahepatic cancer risk has evolved rapidly over the past five years, with multiple large meta-analyses now demonstrating a consistent positive signal across cancer types and study populations. The Zhou et al[37] meta-analysis of 18 cohort studies (approximately 16.7 million participants) found significantly elevated MASLD-associated risk for gastric, colorectal, pancreatic, biliary tract, thyroid, urinary system, breast, and female genital organ cancers, with hazard ratios ranging from 1.17 to 1.47. The Chan et al[52] meta-analysis of 129 studies reported a pooled hazard ratio of 1.54 (95%CI: 1.35-1.76) for all cancers among MASLD patients compared with non-MASLD controls. Importantly, the Celsa et al[53] meta-analysis of 24 cohort studies (approximately 11.6 million individuals) found that extrahepatic cancer incidence had the lowest between-study heterogeneity (I² = 0%) of all outcomes examined, indicating that this association is remarkably consistent across geographic, methodological, and populational variation. The Mantovani et al[12] meta-analysis in Gut reinforces this consistency, with a 1.5- to 2-fold increased GI cancer risk in NAFLD that is “independent of age, sex, smoking, obesity, diabetes, or other potential confounders”.

Extrahepatic cancer in MASLD is also rising in absolute terms over time. The nationwide Korean cohort study by Park et al[54] followed 9298497 individuals (of whom 2500080 were diagnosed with MAFLD) over a median 10.3 years and identified 447880 incident extrahepatic malignancies (6.0% cumulative incidence), with both the diabetic MAFLD [adjusted subdistribution hazard ratio (aSHR) 1.13] and lean MAFLD (aSHR 1.12) subtypes carrying elevated risk. A prospective cohort study by Peng et al[55] similarly found rising cancer incidence in MASLD populations over follow-up, and an earlier systematic review by Liu et al[11] documented the same trend in pooled NAFLD analyses. Collectively, this evidence positions extrahepatic cancer as a first-tier complication of MASLD rather than a secondary or speculative association.

Young-onset and early-age MASLD and cancer risk

Earlier-onset MASLD carries disproportionately elevated cancer risk, a pattern consistently observed across recent large nationwide cohorts. In the matched cohort study by Liu et al[56], NAFLD onset before age 45 was associated with an average hazard ratio of 1.52 (95%CI: 1.09-2.12) for incident cancer, with risk declining as onset age increased. In patients under 45, 17.83% of cancer risk was attributable to NAFLD on population-attributable fraction analysis. The nationwide Korean cohort by Moon et al[57] (2877245 young adults aged 20-39) confirmed a significantly elevated all-cancer risk in young-adult MASLD (HR 1.19, 95%CI: 1.16-1.22), with cancer risk increasing in a graded, dose-dependent fashion as the number of accompanying cardiometabolic risk factors rose.

A finding of high clinical relevance comes from the Chung et al[58] cohort of 3536172 young adults followed over a median of 10.6 years. Persistent MASLD carried the highest cancer risk (HR 1.15, 95%CI: 1.13-1.18), while resolved MASLD showed no significant difference in cancer risk vs controls (HR 1.02, 95%CI: 0.98-1.05). This dynamic relationship provides direct evidence that MASLD is a modifiable cancer risk factor, since regression of MASLD appears to return cancer risk towards baseline. The finding supports an intervention paradigm centered on reversing hepatic steatosis early in the disease course. Given rising global MASLD prevalence among children and young adults, these findings have substantial public health implications for both screening and early therapeutic intervention.

Fibrosis severity and cancer risk gradient

The relationship between liver fibrosis stage and extrahepatic cancer risk in MASLD is asymmetric and clinically important. As developed in detail in the subsection on fibrosis severity as a cancer risk modifier, advanced non-cirrhotic fibrosis (F3) confers disproportionate extrahepatic cancer and vascular risk while cirrhosis (F4) shifts the risk profile toward liver-related mortality, fibrosis stage is the primary determinant of all-cause mortality, and overall cancer incidence rises across fibrosis stages but is driven chiefly by HCC with only a modest extrahepatic contribution[27-30].

These findings provide direct clinical relevance. Advanced non-cirrhotic fibrosis (F3) should be treated as a high-risk clinical state for extrahepatic cancer, warranting more intensive surveillance discussions even when hepatic outcomes appear stable. Equally important is the recognition that extrahepatic cancer risk in MASLD does not consistently amplify the transition from F3 to F4 and may be partially uncoupled from fibrosis at lower stages. Therefore, liver fibrosis stage alone cannot be used as the sole screening trigger for extrahepatic cancer surveillance in MASLD patients. A comprehensive risk stratification must incorporate metabolic burden, diabetes status, sex, age at onset, and disease duration.

Sex differences and dimorphic cancer risk

MASLD is a sexually dimorphic disease, and its extrahepatic cancer landscape mirrors this biology. Estrogens and androgens, along with the ratio between them, influence both MASLD pathogenesis and the spectrum of hormone-sensitive cancers that emerge as complications, particularly breast, endometrial, and ovarian cancer in women[26]. In the nationwide Korean cohort of 483279 women aged 40-60 by Lee et al[51], MASLD was not significantly associated with overall breast cancer risk; however, among postmenopausal women with BMI 25-30, MASLD was independently associated with elevated risk (adjusted HR 1.203, 95%CI: 1.029-1.407), identifying a clinically relevant subgroup at heightened risk. The nationwide cohort of 2376482 women aged 20-39 (Park et al[46], 2025) demonstrated an adjusted HR of 1.30 (95%CI: 1.16-1.45) for young-onset ovarian cancer in NAFLD, with a clear dose-response across NAFLD severity (severe NAFLD aHR 1.45; P for trend < 0.01).

Mechanistically, these sex-skewed risks reflect the convergence of peripheral aromatization-driven estrogen excess, leptin-mediated proliferative signaling, hyperinsulinemia, and adipokine dysregulation in the metabolic-hepatic milieu described in the subsection on adipose tissue and hormonal dysregulation[26]. In men, the picture is less uniform: MASLD-associated testosterone deficiency may reduce androgen-driven prostate carcinogenesis (consistent with the null or inverse prostate cancer signal observed in pooled analyses; see the discussion of prostate cancer), while shared hyperinsulinemia and gut-liver axis perturbations sustain elevated risk for colorectal and urologic cancers. Clinical risk stratification therefore should be sex-specific: Women with MASLD, particularly postmenopausal women with elevated BMI and young women with severe disease, warrant heightened attention to breast and gynecologic surveillance, while men with MASLD remain primarily at risk for the GI cancers detailed in the GI extrahepatic malignancies section.

MASLD comorbidities and compounding cancer risk

T2DM, obesity, or metabolic syndrome frequently co-occur with MASLD and contribute additively, and sometimes synergistically, to extrahepatic cancer risk. The central question is whether MASLD confers cancer risk independent of these comorbidities, or whether the observed associations are explained by confounding. The Allen et al[35] community-based cohort followed over 21 years provides the clearest evidence. Patients with NAFLD had nearly a 2-fold increase in cancer incidence, predominantly consisting of liver, GI tract, and uterine. Critically, the cancer-risk association was stronger in NAFLD than in obesity alone, demonstrating that NAFLD confers independent oncologic risk beyond shared metabolic factors. The broader mechanistic framework, described by Renehan et al[15], shows that adiposity-driven oncogenic mechanisms, including altered sex hormone metabolism, insulin/IGF-1 bioavailability, and adipokine pathophysiology, are partially modifiable through intentional weight loss.

Among comorbidities, T2DM is the most consistent amplifier of MASLD-associated cancer risk. In the Park et al[41] nationwide BTC cohort, concomitant NAFLD and diabetes were associated with a 47% increase in BTC risk. The Golabi et al[59] analysis of NHANES III with follow-up through 2019 showed that NAFLD subjects with T2DM had the highest cumulative mortality among NAFLD phenotypes (41.3%). The 2026 ADA Standards of Care explicitly acknowledge this overlap, noting that CVD remains the leading cause of death in MASLD patients, “followed by certain extrahepatic cancers (primarily GI, breast, and gynecologic cancer)”, framing the T2DM-MASLD connection as clinically relevant for cancer risk management[38]. The complementary 2025 ADA consensus report from Cusi et al[39] reinforces this framework and calls for fibrosis screening as a new standard of care in patients with prediabetes or T2DM. Integrated cardiometabolic-oncologic risk assessment, particularly in patients with both MASLD and T2DM, represents an emerging clinical priority[60].

DIAGNOSTIC APPROACHES AND SURVEILLANCE IMPLICATIONS

Identifying at-risk patients: Biomarkers and non-invasive tools

Effective cancer risk stratification in MASLD requires non-invasive tools that can identify high-risk individuals from within the large MASLD population. The FLI, a validated composite of triglycerides, BMI, waist circumference, and gamma-glutamyl transferase, has been shown in United Kingdom Biobank analyses to stratify not only the cross-sectional presence of NAFLD but also incident cardiometabolic disease, hepatic malignancy, “specific metabolism-related malignancies”, and all-cause mortality[61]. When combined with either the NAFLD fibrosis score or FIB-4, FLI independently predicts mortality risk[61]. The clinical implication is that simple, widely available laboratory parameters can flag MASLD patients warranting enhanced cancer surveillance, even in primary care settings where transient elastography may not be accessible. Importantly, the Ratziu et al[62] validation study confirmed that the diagnostic accuracy of FIB-4 and vibration-controlled transient elastography is nearly identical when applied to NAFLD and MASLD defined populations, allowing historical NAFLD risk-stratification literature to be extrapolated without re-validation.

Beyond conventional biomarkers, omics-based technologies, including genomics, transcriptomics, metabolomics, and proteomics, are rapidly developing tools that “show great potential for discovering non-invasive markers” of MASLD-associated malignancies in both cirrhotic and non-cirrhotic patients[63]. Liquid biopsy approaches incorporating circulating tumor DNA, microRNAs, and EV-derived cargo (discussed in the subsection on hepatocyte-derived EVs and systemic crosstalk) may eventually allow individualized cancer surveillance in MASLD, although none of these approaches are yet clinically validated for routine use. In the interim, FIB-4 plus FLI represents the most pragmatic available framework for identifying MASLD patients at elevated cancer risk.

Current surveillance gaps and opportunities

Despite the developing evidence linking MASLD to extrahepatic malignancy, no consensus-endorsed cancer surveillance protocol specific to MASLD populations currently exists, representing an unmet clinical need. The Thomas et al[9] review explicitly highlights this gap, noting that “almost 30% of the world’s adult population has NAFLD” and that deaths from extrahepatic cancers in this population already exceed those from HCC, yet “no established extrahepatic cancer surveillance guidance” exists for NAFLD/MASLD cohorts. The Kalligeros et al[64] synthesis describes understanding MASLD-cancer mechanisms as “crucial for developing targeted screening and prevention strategies”, and the Kim and Seki[17] review underscores the timeliness of integrating hepatic microenvironmental and immune-response insights into clinical risk frameworks.

In the absence of MASLD-specific protocols, several practical measures are available within current clinical structures. Enhanced adherence to existing age-and-sex-appropriate cancer screening guidelines should be strongly emphasized in patients with MASLD. These include colonoscopy for CRC, mammography for breast cancer, and urologic surveillance for at-risk men. A further option is risk-stratified extension of standard screening intervals for MASLD patients with concentrated risk profiles, such as earlier colonoscopy in MASLD patients with diabetes, postmenopausal women with MASLD and BMI 25-30 for breast surveillance. Although, this requires guideline development and evidence support through more studies before widespread implementation. Finally, integrated cardiometabolic-oncologic risk assessment that links hepatology, endocrinology, and primary care offers a feasible structural approach to operationalize MASLD as a multisystem disease with oncologic implications[38,39]. Particular attention is warranted for lean MASLD, in which the colorectal cancer association may exceed that observed in obese individuals (see the discussion of colorectal cancer). With such patients unlikely to be flagged by body mass index-based triggers, colonoscopic surveillance decisions in this subgroup should rest on hepatic steatosis and metabolic criteria rather than adiposity alone.

Management of MASLD as cancer risk reduction

A pragmatic implication of the evidence reviewed throughout this manuscript is that effective MASLD management may constitute a meaningful cancer-risk-reduction strategy, particularly given that MASLD is a modifiable cancer risk factor (as established in the subsection on young-onset and early-age MASLD and cancer risk)[58]. The strongest anchor for this principle is that resolution of MASLD returns cancer risk toward that of unaffected individuals, whereas persistent disease retains the highest risk[58]; each intervention below is therefore considered specifically for its capacity to reverse hepatic steatosis and the systemic metabolic milieu that drives extrahepatic carcinogenesis. The first-line intervention remains lifestyle modification: Weight loss of 3%-5% via dietary and exercise interventions improves hepatic steatosis with reversal of insulin resistance, while weight loss exceeding 10% achieves improvement in hepatic fibrosis[60]. Aerobic exercise of about 150 minutes per week of moderate-intensity [3-6 metabolic equivalent tasks (METs)] or 75-150 minutes per week of vigorous-intensity (> 6 METs) is recommended by the American Association for the Study of Liver Diseases guidance. In addition, 2-3 sessions of resistance training are also recommended. In patients with cirrhosis both aerobic and anaerobic exercise have shown to reduce portal pressure[65]. Patients with MASLD and cirrhosis should also focus on increased daily protein intake to improve frailty and reduce sarcopenia[66]. Some studies have shown that a Mediterranean dietary pattern is preferred in MASLD due to its low glycemic effects and cardiometabolic benefits[60]. Bariatric surgery improves steatosis, hepatic inflammation, and fibrosis through weight loss and microbiome modulation, providing rationale for surgical management in selected patients with severe obesity and MASLD[60].

The pharmacotherapeutic landscape has expanded substantially. Glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide) achieve 2.0-11.4 kg weight loss with HbA1c reductions of 0.66%-2.3%, and tirzepatide (a dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist) achieves 15%-20.9% weight loss from baseline[60]. Semaglutide and resmetirom (a thyroid hormone receptor-β agonist) are now conditionally United States Food and Drug Administration approved for adults with metabolic dysfunction-associated steatohepatitis and moderate-to-advanced fibrosis[44]. Farnesoid X receptor agonists (e.g., obeticholic acid) reduce hepatic inflammation, fibrosis, and improve insulin sensitivity[60]. Reviews by Targher et al[67] and Stefan et al[16] highlight that the most effective non-pharmacological intervention remains weight loss, while pharmacotherapy is increasingly central to MASLD care as the disease’s metabolic, cardiovascular, and oncologic burden becomes better understood.

While direct evidence that MASLD pharmacotherapy reduces extrahepatic cancer incidence is still emerging, the Chung et al[58] finding that resolved MASLD normalizes cancer risk provides indirect but powerful support for the principle that MASLD reversal constitutes cancer prevention. Notably, GLP-1 receptor agonists have shown signals of reduced incident cancer in obesity and T2DM populations more broadly, and the 2026 Wu et al[33] Delphi consensus explicitly identifies GLP-1 receptor agonists, weight loss, and bariatric surgery as risk-reduction strategies for MASLD-associated CRC.

Limitations

Several limitations temper these conclusions. The evidence base is heterogeneous in disease definition, spanning historical non-alcoholic fatty liver disease, metabolic dysfunction-associated fatty liver disease, and current MASLD criteria, and most studies rely on non-invasive surrogates such as the FLI or ultrasonography rather than histology, introducing exposure misclassification. Residual confounding by obesity, type 2 diabetes mellitus, smoking, and shared metabolic factors cannot be fully excluded in observational designs, which preclude causal inference. Much of the strongest signal, particularly for biliary tract, thyroid, ovarian, and young-onset cancers, derives from Asian and predominantly Korean nationwide cohorts, limiting generalizability to Western and other populations. Several associations rest on single cohorts or show between-study heterogeneity, and site- and histology-specific estimates remain sparse. These constraints argue for cautious interpretation of effect magnitudes and for prospective, multiethnic validation before MASLD-specific surveillance can be formally recommended.

CONCLUSION

MASLD is no longer a disease confined to the liver. The evidence reviewed here demonstrates a consistent and clinically meaningful association between MASLD and an expanded spectrum of extra-hepatic malignancies. These span GI cancers, most robustly colorectal cancer, with growing data for pancreatic, esophagogastric, and BTCs, as well as non-GI cancers, including breast, gynecologic, thyroid, urinary system, and lung cancers. The oncologic risk landscape of MASLD is driven by a convergence of systemic metabolic pathways, including insulin resistance, chronic inflammation, lipotoxicity, gut dysbiosis, and hormonal dysregulation, many of which are addressable through therapeutic intervention.

Rising trends in MASLD prevalence globally portend a parallel increase in associated cancer burden, with particular concern for younger populations and those with advanced hepatic fibrosis. Sex-specific differences in malignancy risk require tailored consideration. Despite the growing body of evidence, dedicated MASLD-specific cancer surveillance guidelines remain absent, representing an important unmet clinical need. Future prospective studies should prioritize establishing causal relationships, defining fibrosis thresholds for cancer screening initiation, and evaluating sex-stratified risk prediction tools. A multidisciplinary approach integrating hepatology, oncology, endocrinology, and primary care would be a key consideration to translating this evidence into actionable clinical practice.