Dietary monounsaturated fatty acid facilitates lipid droplet turnover through chaperone HSP90A-mediated lysosomal degradation of PLIN2 in hepatocellular carcinoma

Dietary lipids are emerging as critical regulators of tumor metabolism. However, the understanding of how dietary lipid molecules remodel tumor metabolism to drive malignancy remains incomplete. In this study, we revealed that monounsaturated fatty acids (MUFAs) selectively promote hepatocellular carcinoma (HCC) progression by rewiring lipid droplet (LD) metabolism through a selective autophagy mechanism. Proteomic profiling of LD-binding proteins identified HSP90A (heat shock protein 90 alpha) as a MUFA-induced factor translocated to LDs. The recruitment of HSP90A subsequently initiated the breakdown of LDs, releasing FAs from LDs for mitochondrial respiration. Mechanistically, MUFAs facilitated the specific interaction between HSP90A and PLIN2 to stimulate the degradation of PLIN2 in non-canonical lysosomal pathway. Although this process requires LAMP2A, similar to chaperone-mediated autophagy, it relies on HSP90 rather than HSPA8/HSC70 for the recognition of PLIN2. Targeting HSP90A dampened LD mobilization and effectively prevented orthotopic HCC tumor growth induced by dietary MUFA. Collectively, our data demonstrated that dietary MUFA exhibits a distinctive tumor-promoting effect on HCC through HSP90A-mediated LD mobilization and suggested that targeting HSP90A-regulated autophagy may serve as a therapeutic strategy for the treatment of HCC.<b>Abbreviation</b>: Apo: apoptozole; Baf A1: bafilomycin A₁; CMA: chaperone-mediated autophagy; CQ: chloroquine; DGAT: diacylglycerol; FA: fatty acid; HCC: hepatocellular carcinoma; HFD-OA: high-fat diet rich in olive oil; HFD-PA: high-fat diet rich in palm oil; HSP90A: heat shock protein 90 alpha; LA: linoleic acid; LDs: lipid droplets; MUFA: monounsaturated FA; NAFLD: nonalcoholic fatty liver disease; NCD: normal chow diet; OA: oleic acid; PA: palmitic acid; PLIN: perilipin; POA: palmitoleic acid; PUFA: polyunsaturated FA; SA: stearic acid; SFA: saturated FA; TG: triglyceride.