Reconsidering the role of metabolic dysfunction-associated steatotic liver disease in pancreatic cancer progression

Abstract

The liver is the most common site of metastasis in pancreatic cancer, and host metabolic conditions have increasingly been proposed as modifiers of tumor dissemination and survival. Metabolic dysfunction-associated steatotic liver disease (MASLD) has attracted particular attention because of its high prevalence and its documented effects on hepatic inflammation, lipid metabolism, and immune regulation. On this basis, it has been hypothesized that a steatotic liver may provide a permissive microenvironment for metastatic seeding. However, emerging large-scale real-world clinical evidence challenges this assumption. In a cohort of more than two thousand patients with pancreatic cancer, steatosis defined by the hepatic steatosis index was not independently associated with liver metastasis at diagnosis, the subsequent development of hepatic metastases, or overall survival. These findings suggest that, despite strong biological plausibility, metabolic liver disease may not represent a dominant driver of metastatic patterns or prognosis in pancreatic cancer. From a gastroenterology and oncology perspective, this discrepancy underscores the need to distinguish mechanistic hypotheses from clinically meaningful risk modifiers. Reframing MASLD as a background metabolic comorbidity rather than a key determinant of metastatic risk may help refine patient stratification, avoid overinterpretation of incidental hepatic steatosis in clinical practice, and redirect future research toward more actionable tumor-intrinsic and host-tumor interaction pathways.

Key Words: Pancreatic cancer; Liver metastasis; Metabolic dysfunction-associated steatotic liver disease; Tumor microenvironment; Prognosis

Core Tip: Metabolic dysfunction-associated steatotic liver disease is biologically linked to hepatic inflammation and immune modulation, yet emerging real-world evidence indicates that it is not an independent determinant of liver metastasis or survival in pancreatic cancer. Clinically, metabolic dysfunction-associated steatotic liver disease should be interpreted as a contextual metabolic comorbidity rather than a decisive prognostic factor, avoiding overinterpretation of incidental hepatic steatosis in risk assessment.

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide, characterized by aggressive biological behavior, early dissemination, and extremely poor survival outcomes[1-3]. Liver metastasis represents the dominant metastatic pattern in PDAC and is a major determinant of mortality, with the majority of patients either presenting with or eventually developing hepatic involvement during the disease course[4,5]. Given the limited efficacy of current systemic therapies, increasing attention has been directed toward host-related factors that may modulate metastatic spread and prognosis[6-8].

In parallel, metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as nonalcoholic fatty liver disease (NAFLD), has emerged as a global health burden affecting a substantial proportion of adults[9]. Beyond its hepatic manifestations, MASLD is now recognized as a multisystem metabolic disorder closely linked to insulin resistance, dyslipidemia, chronic inflammation, and immune dysregulation[10,11]. Epidemiological studies consistently demonstrate that MASLD is associated with an increased risk of several extrahepatic malignancies, including pancreatic cancer, independent of obesity and diabetes[12-15]. However, an increased risk of cancer incidence does not necessarily imply a comparable influence on tumor progression, metastatic patterns, or survival after diagnosis.

These observations have fueled the hypothesis that MASLD may not only increase pancreatic cancer incidence but also influence disease progression and metastatic behavior[16]. From a biological perspective, a steatotic liver exhibits profound alterations in lipid metabolism, inflammatory signaling, and immune surveillance, all of which could theoretically facilitate tumor cell seeding and outgrowth[17]. Experimental models have shown that metabolic liver disease may contribute to the formation of a pro-metastatic hepatic niche through pathways involving lipid metabolism remodeling, endoplasmic reticulum stress, and immune microenvironment reprogramming[18-20]. Additional mechanistic studies implicate specific signaling axes, such as migration inhibitory factor (MIF)-cluster of differentiation (CD) 44 and CX3CL1/CX3CR1, in linking metabolic dysfunction to enhanced liver colonization by pancreatic cancer cells[21].

However, despite this strong biological plausibility, clinical evidence supporting MASLD as a key determinant of liver metastasis or prognosis in PDAC remains inconsistent. A recent large real-world cohort study reported that MASLD, defined using the hepatic steatosis index, was not independently associated with synchronous liver metastasis, metachronous hepatic metastasis, or overall survival in patients with pancreatic cancer[22]. While several retrospective analyses and population-based studies suggest that metabolic syndrome, insulin resistance, or steatotic liver disease may be associated with poorer outcomes[23-26], other real-world investigations report neutral or non-significant associations between NAFLD/MASLD and survival or metastatic patterns after adjustment for tumor-related factors[27]. Moreover, emerging data indicate that certain metabolic indices may show paradoxical relationships with liver metastasis risk, underscoring the complexity of metabolic influences in advanced pancreatic cancer[28].

This divergence between mechanistic expectations and clinical observations raises an important question: Does metabolic liver disease act as a dominant driver of pancreatic cancer progression, or merely as a background metabolic modifier? Accordingly, the central objective of this article is to critically examine whether MASLD should be interpreted as a dominant determinant of liver metastasis and prognosis or rather as a contextual metabolic modifier in pancreatic cancer. Addressing this issue is critical for refining risk stratification, avoiding overinterpretation of metabolic phenotypes. It also helps prioritize research directions with genuine translational value.

In this article, we critically re-examine the role of MASLD in pancreatic cancer progression, with a particular focus on liver metastasis and prognosis. By integrating epidemiological data, mechanistic insights, and real-world clinical evidence, we aim to distinguish biological plausibility from clinically meaningful impact and to reframe MASLD within a more nuanced oncologic context. A conceptual overview contrasting prevailing hypotheses with emerging real-world evidence and the underlying biological mechanisms is summarized in Figure 1.

Figure 1 Reconsidering the role of metabolic dysfunction-associated steatotic liver disease in pancreatic cancer progression. MASLD: Metabolic dysfunction-associated steatotic liver disease.

METABOLIC LIVER DISEASE AND PANCREATIC CANCER: EPIDEMIOLOGICAL LINKS AND UNRESOLVED QUESTIONS

A growing body of epidemiological evidence has established MASLD, previously termed NAFLD, as a systemic condition extending beyond the liver[29-31]. Large population-based cohorts and meta-analyses consistently report an increased incidence of pancreatic cancer among individuals with MASLD or NAFLD, independent of traditional risk factors such as obesity and diabetes[11-14]. These findings have reshaped the conceptualization of MASLD as a multisystem disease with oncogenic implications.

However, while the association between MASLD and pancreatic cancer incidence appears relatively robust, studies focusing on cancer incidence should be distinguished from those evaluating post-diagnosis outcomes, and its role in shaping disease behavior after diagnosis particularly liver metastasis and survival remains controversial. Several retrospective studies and registry-based analyses suggest that metabolic syndrome components, insulin resistance, and steatotic liver disease correlate with poorer outcomes in pancreatic cancer[25,26]. In contrast, other real-world datasets fail to demonstrate a clear survival disadvantage attributable to NAFLD or MASLD, or even report neutral associations after adjustment for confounders[27]. This discrepancy highlights a critical gap between population-level cancer risk and clinically meaningful modifiers of metastatic progression.

BIOLOGICAL MECHANISMS LINKING MASLD TO HEPATIC METASTASIS: STRONG PLAUSIBILITY, LIMITED TRANSLATION

Metabolic reprogramming and lipid-driven tumor support

Experimental studies suggest compelling mechanistic explanations for why a steatotic liver might favor metastatic colonization[32,33]. To enhance conceptual clarity, the key mechanistic domains discussed in this section include metabolic reprogramming, immune microenvironment remodeling, and lipid-immune crosstalk within the hepatic niche[34,35]. MASLD is characterized by altered lipid metabolism, endoplasmic reticulum stress, and chronic inflammatory signaling[36,37]. These alterations may support tumor cell survival and growth within the hepatic niche[18-20]. Transcriptomic analyses of pancreatic cancer liver metastases reveal enrichment of lipid metabolism and endoplasmic reticulum stress-related gene signatures associated with immune suppression and adverse prognosis[19].

Immune microenvironment remodeling

MASLD-associated immune dysregulation represents another proposed mechanism. Preclinical models demonstrate that steatotic livers exhibit increased immunosuppressive macrophages, impaired cytotoxic T-cell responses, and enhanced cancer stemness, collectively potentially lowering the barrier to metastatic seeding[38]. Chemokine axes such as CX3CL1/CX3CR1 have been implicated in obesity-driven recruitment of pancreatic cancer cells to the liver[21].

Molecular signaling pathways

Several signaling pathways potentially linking metabolic dysfunction to metastasis have been identified, including the macrophage MIF-CD44 axis, insulin-phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling, and lipid-immune crosstalk at the tumor-stroma interface[39]. These findings collectively support the concept that MASLD can generate a biologically permissive hepatic microenvironment.

Nevertheless, the majority of these data derive from animal models or molecular profiling studies, raising questions regarding their translatability to heterogeneous human populations with advanced pancreatic cancer. These mechanistic-clinical discrepancies are conceptually integrated in Figure 1 to facilitate visual synthesis of the proposed framework. Notably, most of these mechanistic insights are derived from preclinical or molecular studies and should be interpreted as hypothesis-generating rather than definitive causal evidence.

REAL-WORLD CLINICAL EVIDENCE: REASSESSING THE MAGNITUDE OF EFFECT

Contrary to expectations derived from mechanistic studies, large real-world cohorts increasingly suggest that MASLD is not an independent driver of liver metastasis or survival in pancreatic cancer. Analyses incorporating steatosis indices, imaging-based assessments, or diagnostic coding demonstrate that hepatic steatosis does not consistently predict synchronous liver metastasis, metachronous hepatic spread, or overall survival once tumor stage and treatment variables are considered[27].

Importantly, metabolic indices themselves show complex and sometimes paradoxical associations. For example, the triglyceride-glucose index commonly regarded as a marker of insulin resistance has been reported to be inversely associated with liver metastasis risk in pancreatic cancer, challenging simplistic assumptions about metabolic dysfunction uniformly promoting dissemination[28]. This paradoxical pattern may reflect the complex, stage-dependent, and context-specific nature of metabolic indices in advanced malignancy, where cachexia, metabolic reprogramming, and reverse epidemiology phenomena can alter the conventional interpretation of insulin resistance-related markers[40,41]. Similarly, body composition analyses suggest that specific fat and muscle distributions, rather than liver steatosis perse, may better capture clinically relevant metabolic effects on survival[42,43].

These findings imply that while metabolic dysregulation undoubtedly influences tumor biology, its net clinical impact on metastatic patterns may be modest relative to dominant tumor-intrinsic factors[44]. Overall, current real-world studies consistently show neutral or context-dependent associations between MASLD/steatosis and liver metastasis, survival, or disease progression after adjustment for tumor burden, stage, and treatment-related factors[45].

Several alternative explanations may account for the neutral or inconsistent clinical correlations observed in real-world cohorts. First, the aggressive natural history of pancreatic cancer and high early mortality may introduce a competitive mortality effect, potentially obscuring the long-term influence of metabolic liver disease on metastatic trajectories[46,47]. Second, advanced-stage presentation at diagnosis may mask subtle host-metabolic effects, as tumor burden and systemic disease biology dominate clinical outcomes[48]. Third, substantial treatment heterogeneity across real-world datasets including differences in chemotherapy regimens, supportive care, and surgical eligibility may dilute the detectable impact of metabolic comorbidities[49]. In addition, cancer-associated cachexia and dynamic metabolic alterations during disease progression may confound baseline metabolic indices, while potential reverse epidemiology phenomena in advanced malignancy further complicate interpretation[50,51]. Collectively, these factors suggest that clinical neutrality should not be equated with biological irrelevance but rather interpreted within the complex context of disease stage, treatment, and systemic metabolic remodeling (Table 1).

Table 1 Conceptual integration of biological plausibility and clinical evidence regarding metabolic dysfunction-associated steatotic liver disease in pancreatic cancer progression.

Domain	Proposed effect of MASLD	Supporting biological rationale	Clinical evidence pattern	Interpretation
Hepatic metabolic reprogramming	Promotes metastatic colonization	Lipid accumulation, ER stress, altered energy metabolism favor tumor cell survival	Inconsistent or neutral association with liver metastasis	Biological effect exists but limited clinical impact
Immune microenvironment remodeling	Facilitates immune evasion	Increased immunosuppressive macrophages, reduced cytotoxic T-cell activity	No consistent impact on survival after adjustment	Likely context-dependent rather than dominant
Inflammatory signaling	Enhances tumor-promoting inflammation	Chronic low-grade inflammation and cytokine activation	Weak or non-independent association with prognosis	May act as a background amplifier
Insulin resistance and metabolic signaling	Drives tumor aggressiveness	Activation of PI3K/AKT/mTOR and related pathways	Mixed findings across studies	Effect modified by disease stage and cachexia
Systemic metabolic state	Alters host-tumor interaction	Dyslipidemia, metabolic syndrome, altered nutrient availability	Paradoxical or bidirectional associations observed	Reflects complex systemic adaptation
Body composition and energy balance	Influences survival and progression	Sarcopenia, visceral adiposity, metabolic reserve	More consistent association than liver steatosis alone	More clinically relevant than MASLD perse
Overall clinical role			Predominantly neutral after adjustment	MASLD acts as a modifier rather than a determinant

MASLD: Metabolic dysfunction-associated steatotic liver disease; ER: Endoplasmic reticulum; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin.

PROGNOSTIC IMPLICATIONS: METABOLIC DISEASE AS A MODIFIER, NOT A DETERMINANT

The prognostic literature further reinforces the need for recalibration. While metabolic syndrome and insulin resistance have been associated with worse outcomes in selected cohorts[52], the independent contribution of MASLD remains inconsistent across studies. Some large inpatient analyses report no increase in short-term mortality among pancreatic cancer patients with NAFLD, despite higher healthcare utilization[27].

Nomograms and predictive models for liver metastasis and early mortality in pancreatic cancer increasingly emphasize tumor burden, performance status, and treatment strategies, with metabolic variables playing a secondary or contextual role[5,53,54]. Collectively, these observations suggest that MASLD functions more plausibly as a background comorbidity that modulates systemic inflammation and metabolism rather than as a decisive prognostic determinant.

CLINICAL AND RESEARCH IMPLICATIONS: REFRAMING PRIORITIES

From a gastroenterology and oncology perspective, overemphasizing MASLD as a metastatic driver may blur the distinction between biological plausibility and clinical relevance. The current evidence supports several practical considerations: Patient stratification should not rely on MASLD status alone to estimate metastatic risk or survival in pancreatic cancer[55]. Research focus should shift toward identifying metabolic pathways that directly influence treatment response or immune evasion rather than assuming uniform pro-metastatic effects of steatosis[56]. Future studies must incorporate standardized MASLD definitions, longitudinal follow-up, and rigorous adjustment for confounders to clarify context-dependent effects[57].

From a practical clinical perspective, MASLD status may be more appropriately integrated as a contextual host factor rather than a decisive determinant in multidisciplinary tumor board discussions[58]. Current evidence does not support using hepatic steatosis alone to upstage metastatic risk; however, its presence may still inform comprehensive patient assessment, including metabolic reserve, chemotherapy tolerance, and perioperative risk stratification[59]. In addition, incidental hepatic steatosis detected on staging imaging should be interpreted cautiously, as it may reflect underlying metabolic comorbidity rather than a direct pro-metastatic hepatic niche[60]. Such an approach aligns with real-world decision-making by balancing biological plausibility with clinically actionable evidence.

Emerging interventions targeting metabolic health including bariatric surgery and pharmacologic metabolic modulation may influence cancer risk at the population level, but their impact on metastatic progression after pancreatic cancer diagnosis remains to be established[61].

CONCLUSION

The accumulated literature illustrates a recurring theme in translational oncology: Strong mechanistic plausibility does not necessarily translate into substantial and clinically actionable impact. While MASLD profoundly reshapes hepatic metabolism and immunity, current real-world evidence indicates that it is unlikely to be a primary and independent determinant of liver metastasis or prognosis in pancreatic cancer. Recognizing this distinction allows for more precise risk modeling and redirects attention toward tumor-intrinsic biology and actionable host-tumor interactions that truly govern disease progression. Importantly, several unresolved questions remain, including the heterogeneity of metabolic phenotypes within MASLD, context-dependent effects across disease stages, and the limited granularity of current real-world datasets in capturing dynamic host-tumor-metabolic interactions. Future research should prioritize prospective, longitudinal cohorts with standardized MASLD definitions, integrated metabolic and oncologic phenotyping, and treatment-stratified analyses to clarify the context-dependent and stage-specific clinical relevance of metabolic liver disease in pancreatic cancer progression. Such efforts will help bridge the gap between mechanistic plausibility and robust, clinically meaningful impact.