Lipid Droplet Accumulation in Cancer: Targeting Lipophagy as a Therapeutic Strategy

Lipid droplets (LDs) are dynamic organelles involved in cellular lipid storage, trafficking, and metabolic regulation. Recent studies highlight their altered accumulation in various cancer types, correlating with tumorigenesis, progression, and metastasis. The accumulation of LDs in cancer cells contributes to oncogenic lipid metabolism, which promotes cell proliferation, resistance to apoptosis, and adaptation to tumor microenvironment stresses, including hypoxia and nutrient deprivation. Lipophagy, a specialized form of autophagy responsible for the selective degradation of LDs, has emerged as a potential target for cancer therapy due to its role in modulating cellular lipid reserves and maintaining energy balance. This review explores the molecular mechanisms underlying LD accumulation in cancer and the regulation of lipophagy, examining the implications of lipid storage modulation on cancer cell survival and metabolic adaptation. We also discuss therapeutic strategies aimed at targeting lipophagy pathways, such as inhibition of key lipophagic regulators and combination approaches with established chemotherapies, to improve cancer treatment efficacy. Understanding the intersection of lipid metabolism, LD biogenesis, and lipophagy may offer novel therapeutic avenues, providing more personalized and effective interventions for lipid-metabolism-driven cancers. Keywords: Lipid droplets; Lipophagy; Cancer metabolism; Autophagy; Lipid metabolism; Therapeutic targets in cancer; Lipid accumulation in tumors