Hemadri_2025_Cell.Biol.Toxicol_41_149

Lipolysis, a tightly regulated metabolic process, is hijacked by cancer cells to meet their energy and biosynthetic demands under stress. Central to this process is hormone-sensitive lipase (HSL), a key enzyme that orchestrates lipid mobilization by hydrolyzing diacylglycerols into free fatty acids (FFAs). This review explores the pivotal and multifaceted role of HSL in cancer metabolism, focusing on its dual function acting as both a tumor promoter and suppressor depending on the cancer type and microenvironment. Lipolysis, the breakdown of triglycerides into free fatty acids (FFAs), is essential for maintaining energy homeostasis, and is co-opted by tumor cells to fuel growth. Enzymes such as ATGL, HSL, and MGL synergistically regulate lipolysis, with HSL being the driver in this process. Dysregulation of HSL can either promote or inhibit cancer growth, depending on the tumor type. We examine how deregulated HSL activity contributes to tumor progression, metastasis, and therapy resistance through metabolic reprogramming, particularly in the context of cancer-associated adipocytes (CAAs) and fibroblasts (CAFs). CAAs and CAFs within the tumor microenvironment modulate lipid metabolism, influencing tumor progression. The review also discusses the interplay between HSL and oncogenic signaling pathways, its regulation by hormonal and transcriptional networks, and its impact on immune modulation and cachexia. Finally, we evaluate the therapeutic potential of targeting HSL, emphasizing the need for cancer-type-specific strategies to exploit its vulnerabilities without exacerbating metabolic imbalance. By decoding HSL's role in cancer energetics, this review provides a foundation for novel interventions aimed at disrupting tumor lipid metabolism. Although, therapeutic strategies targeting lipolytic enzymes, such as HSL holds promise, this review also iterates the requisite for context specific considerations for successful application.