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

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.