Galectin-1 exacerbates hepatic steatosis by impairing autophagy via interaction with FIP200.

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains incompletely understood, particularly the regulatory mechanisms linking autophagy dysregulation to disease progression. While impaired hepatic autophagy is known to contribute to NAFLD, the upstream factors that suppress autophagic flux under metabolic stress are not well defined. In this study, we demonstrate that galectin-1 (Gal-1) acts as a key mediator of hepatic steatosis and metabolic dysfunction by directly inhibiting autophagy. Surprisingly, overexpression of Gal-1 in mice is sufficient to trigger a series of pathological features similar to those of NAFLD, including hepatic steatosis, dyslipidemia, and insulin resistance, even in the absence of dietary challenges. Proteomic profiling revealed that Gal-1 induces a pronounced blockade of autophagic flux, evidenced by p62 accumulation and impaired LC3-II conversion. Mechanistically, Gal-1 binds the core autophagy scaffold protein FIP200, disrupting ULK complex assembly and further suppressing FIP200 expression at both transcriptional and post-translational levels. Structural mapping and binding studies identified a specific bipartite interaction interface involving Gal-1 residues TYR120/PHE134 and the claw domain of FIP200, with a binding affinity (Kd = 113.1 μM) critical for its autophagy-inhibitory function. Crucially, point mutations disrupting this interaction abolished Gal-1-mediated autophagy suppression and insulin resistance in cellular models. Our results uncover the Gal-1-FIP200 axis as a previously unrecognized regulatory node in NAFLD pathogenesis, offering a promising target for therapeutic intervention in metabolic liver disease.