Potential role of leptin in colorectal cancer liver metastasis involving lipid metabolic reprogramming and immunosuppressive macrophage polarization.

Liver metastasis, a hallmark of advanced Colorectal cancer (CRC), represents the leading cause of mortality in affected patients. While surgical resection of primary tumors and metastatic lesions remains the gold-standard therapeutic intervention, only 10–20% of patients with hepatic metastases qualify for curative resection, underscoring the critical need for novel therapeutic strategies. Through integrated bioinformatics analysis, we identified Leptin (LEP) as a potential candidate gene associated with colorectal cancer liver metastasis (CRLM). Functional analyses including colony formation, wound healing and cross-well migration indicated that LEP overexpression was associated with enhanced proliferation, invasion and metastasis potential of CRC cells, and vice versa. Mechanistically, Nile Red lipid staining revealed potential lipid metabolic alterations linked to LEP levels in CRC cells. In vivo, a CRLM murine model suggested the potential involvement of LEP in promoting hepatic metastasis and inducing tumor-associated macrophage M2 polarization. Immunofluorescence (IF), quantitative real-time PCR (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA) analyses further supported the correlation between LEP and the upregulation of M2-macrophage markers and associated cytokines. These findings suggest that LEP may function as a candidate modulator of CRLM progression through lipid metabolism rewiring and immunosuppressive macrophage polarization, warranting further investigation into its potential as a diagnostic biomarker or therapeutic target for metastatic CRC.