Lipophagy driven by CLN5-BMP-MCOLN1 axis promotes cancer stem cell properties in breast cancer under obese conditions

The progression of obesity‑driven breast cancer malignancy is closely associated with the enrichment of cancer stem cells (CSCs). As a highly tumorigenic subpopulation, CSCs have their stemness maintenance linked to aberrant activation of the autophagy‑lysosome pathway and are highly dependent on lipid metabolism. Therefore, this study aims to elucidate the potential mechanism by which obesity remodels lipid metabolism to drive CSC conversion. Using a diet-induced obese mouse model and an adipocyte-breast cancer cell coculture system, we found that adipocytes delivered lipids to breast cancer cells, promoted lipid droplet storage, activated lipophagy and lysosomal function, enhanced fatty acid β-oxidation (FAO), and facilitated CSC phenotypic conversion. Lipidomic profiling revealed marked accumulation of the lysosome-enriched lipid bis(monoacylglycerol)phosphate (BMP) in breast cancer cells exposed to adipocytes. In both in vivo and in vitro models of lipid overload, the BMP synthase CLN5 was upregulated. CLN5 knockdown suppressed lipophagy and CSC-associated properties, whereas supplementation with recombinant CLN5 or the BMP precursor lysophosphatidylglycerol restored or promoted these effects. Screening of lysosome-related genes further identified the lysosomal channel MCOLN1 as a lipid-overload-responsive regulator, accompanied by activation of TFEB signaling. Targeting MCOLN1 impaired lipid droplet-driven lipophagy and FAO and inhibited breast cancer cell proliferation and invasion in vitro and in vivo. In summary, this study establishes the CLN5-BMP-MCOLN1 axis as a critical pathway for lipophagy driving CSC transformation in obesity-related breast cancer and provides a novel strategy for targeted lipophagy therapy.