Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and adipose tissue loss, systemic inflammation, and poor clinical outcomes, and represents a major unmet clinical need in gastric cancer. Growth Differentiation Factor 15 (GDF15) is a key mediator of cachexia-associated anorexia and tissue wasting; however, the upstream mechanisms regulating its expression in gastric cancer remain poorly defined. Leukemia Inhibitory Factor (LIF), a pleiotropic cytokine implicated in tumor progression and metabolic dysregulation, has emerged as a potential regulator of cachexia-related pathways. Here, we investigated the association between LIF in regulating GDF15 expression and its relationship with metabolic, inflammatory, and body composition alterations in gastric cancer. Transcriptomic profiling of paired neoplastic and non-neoplastic gastric mucosa from 61 gastric cancer patients revealed a significant upregulation of both LIF and GDF15 in tumor tissue, with a strong positive correlation between their expression levels. High GDF15 expression was associated with reduced overall survival, a finding validated in independent TCGA-STAD and ACRG cohorts. Intratumoral bile acid profiling uncovered a marked enrichment of primary bile acids and a depletion of secondary bile acids, resulting in reduced levels of bile acids with endogenous LIF receptor (LIFR) antagonist activity; elevated primary, LIFR non-antagonist bile acids were associated with worse survival outcomes. Clinically, increased LIF and GDF15 expression correlated with weight loss, heightened inflammatory burden, reduced serum protein and albumin levels, and impaired body composition in a sub-cohort of 19 patients. Notably, LIF expression showed a significant inverse association with both lumbar skeletal muscle index (L3SMI) and subcutaneous adipose tissue index (SATI). Mechanistically, experimental models demonstrated that LIF enhances proliferative activity in gastric cancer spheroids and exerts paracrine effects that impair myogenic differentiation and suppress hepatic metabolic gene expression. Collectively, these findings identify the LIF/GDF15 axis as a central driver of cancer-associated cachexia in gastric cancer and highlight LIF signaling as a potential therapeutic target.

Background: Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are immune-mediated cholestatic disorders characterized by progressive biliary inflammation and fibrosis, for which treatment options remain limited, underscoring the need for novel therapeutic targets. The leukemia inhibitory factor (LIF) is an IL-6-related cytokine that dysregulates the communication between epithelial cells and extracellular matrices by binding a heterodimeric complex formed by LIF receptor (LIFR) and gp130. The role of the LIF/LIFR system in PSC and PBC and its potential as a therapeutic target remain unclear. Methods: We investigated LIF/LIFR system alteration in PSC and PBC and assessed the therapeutic potential of LIFR antagonism in a genetic mouse model of PSC (Abcb4-/- mice). Single-cell transcriptomics analyses were performed to evaluate LIF and LIFR expression in human liver samples. Whole liver RNA-seq and immunostaining were used to assess LIF/LIFR levels and correlation with fibrotic and immune markers. The effects of LIFR antagonism were evaluated in vitro using LRI-310, a steroidal LIFR antagonist, on human cholangiocytes, HSCs, endothelial cells, and macrophages. In vivo, LRI-310 was administered to Abcb4–/– mice, and effects on liver injury, cholestasis, fibrosis, leukocyte infiltration, and gene expression were assessed. Results: LIF expression s enriched in human cholangiocytes, while LIFR is predominantly expressed by HSCs, endothelial cells, and macrophages. Whole liver RNAseq analysis and liver sections immunostaining demonstarted that increased LIF expression correlates with expression of markers of hepatic fibrosis and immune activation in PSC and PBC patients. LRI-310, a steroidal LIFR antagonist, attenuated human cholangiocytes activation and expression of inflammatory mediators, as well as the activation of liver sinusoidal cells and hepatic fibroblasts. In Abcb4 −/− mice administration of LRI-310 mitigated liver injury, cholestasis, liver leukocytes infiltration and reduced the expression of biomarkers associated with fibrosis, inflammation, and bile acid dismetabolism. Conclusion: Cholangiocyte-derived LIF promotes the formation of a pro-inflammatory and pro-fibrotic niche centred on damaged cholangiocytes. LIFR antagonism reverses fibrosis and immune dysregulation in Abcb4 ^−/− mice, supporting the development of anti-LIFR therapies in human cholangiopathies.