Lipid droplets (LDs) are involved in various biological events in cells along with their primary role as a storage center for neutral lipids. Excessive accumulation of LDs is highly correlated with various diseases, including metabolic diseases. Therefore, a basic understanding of the molecular mechanism of LD degradation would be beneficial in both academic and industrial research. Lipophagy, a selective autophagy mechanism/LD degradation process, has gained increased attention in the research community. Herein, we sought to elucidate a novel lipophagy mechanism by utilizing the LD-degrading small molecule, SB2301, which activates ubiquitin-mediated lipophagy. Using a label-free target identification method, we revealed that ethanolamine-phosphate cytidylyltransferase 2 (PCYT2) is a potential target protein of SB2301. We also demonstrated that although SB2301 does not modulate PCYT2 function, it induces the cellular translocation of PCYT2 to the LD surface and spatially increases the phosphatidylethanolamine (PE)/phosphatidylcholine (PC) ratio of the LD membrane, causing LD coalescence, leading to the activation of lipophagy process to maintain energy homeostasis.

脂滴 (LD) 参与细胞中的各种生物事件以及它们作为中性脂质储存中心的主要作用。LDs 的过度积累与各种疾病高度相关，包括代谢疾病。因此，对 LD 降解的分子机制有一个基本的了解将有利于学术和工业研究。脂肪吞噬是一种选择性自噬机制/LD 降解过程，越来越受到研究界的关注。在此，我们试图通过利用 LD 降解小分子 SB2301 来阐明一种新的脂肪吞噬机制，该分子激活泛素介导的脂肪吞噬。使用无标记目标识别方法，我们发现乙醇胺-磷酸胞苷酰转移酶 2 (PCYT2) 是 SB2301 的潜在目标蛋白。