Current Research Progress on ABHD5 in Cancers.

Lipid metabolism sits at the heart of tumor initiation, progression, metastasis, and resistance to chemotherapy. Against this background, the regulation of lipid flux has emerged as a fertile ground for anticancer strategies. Chanarin-Dorfman syndrome (CDS), a rare genetic disorder marked by massive lipid droplet accumulation, offers compelling human evidence that α/β-hydrolase domain-containing protein 5 (ABHD5) plays a central role in lipid droplet mobilization through the ATGL axis. This clinical insight has, perhaps unexpectedly, pushed ABHD5 into the spotlight of cancer research. ABHD5 does not behave uniformly across malignancies. In many solid tumors-such as lung, liver, and renal cell carcinoma-it restrains tumor growth. Yet in other settings, notably endometrial cancer, it appears to fuel malignant progression. Colorectal and prostate cancers occupy a more ambiguous middle ground, where ABHD5 can tip the balance in either direction depending on context. Mechanistically, ABHD5 influences lipid homeostasis and cell fate by intersecting with signaling pathways including AMPK/mTOR, AKT, and NF-κB, thereby shaping proliferation, invasion, apoptosis, immune evasion, and drug responsiveness. This review brings together experimental and clinical evidence to map the diverse, sometimes contradictory roles of ABHD5 in cancer. By tracing its context-dependent functions and molecular circuits, we also explore its emerging value as a diagnostic marker and a therapeutic target-one that demands nuance rather than blunt intervention.