Pancreatic-liver crosstalk, novel molecular mediators, and 2025 therapeutic breakthroughs

Table 1 Mechanisms of the pancreas-liver axis vicious cycle

Stage	Core driving factors	Key mechanisms	Pathological effects	Therapeutic entry points	Ref.
Cycle initiation	Enhanced adipose tissue lipolysis, increased FFA influx into the liver	Under obesity and insulin resistance, adipose tissue lipolysis is activated; FFA enter the liver via the portal vein	Hepatic ectopic lipid deposition	Inhibit excessive adipose tissue lipolysis	[41,42]
Hepatic activation	FFA accumulate in the liver and trigger metabolic stress	FFA bind to TLR4 on Kupffer cells, activating innate immunity and releasing pro-inflammatory cytokines	Chronic hepatic inflammation, impaired insulin signaling	Target hepatic inflammatory pathways	[42,43]
Direct attack (pancreas)	Excess circulating FFA taken up by β-cells	FFA induce calcium imbalance, ER stress, mitochondrial damage; activate JNK/p38 MAPK pathways	β-cell dysfunction, apoptosis	Protect β-cells from lipotoxic injury	[42,45]
Indirect attack (pancreas)	Liver releases pathogenic mediators, remotely inducing islet inflammation	sEVs and Fetuin-A activate islet macrophages via TLR4, promoting M1 polarization and cytokine release	Impaired β-cell function, local islet inflammation	Block liver-pancreas communication; target hepatokines	[46-49]
Cycle closure	β-cell dysfunction exacerbates lipid metabolism disorders via feedback	Decreased insulin secretion → reduced inhibition of adipose tissue lipolysis → persistently elevated circulating FFA	Self-reinforcing pathological cycle	Exogenous insulin; enhance β-cell function	[42-46]

FFA: Free fatty acid; ER: Endoplasmic reticulum.