LPCAT3 Inhibitors Remodel the Polyunsaturated Phospholipid Content of Human Cells and Protect from Ferroptosis

LPCAT3 is an integral membrane acyltransferase
in the Lands cycle
responsible for generating C20:4 phospholipids and has been implicated
in key biological processes such as intestinal lipid absorption, lipoprotein
assembly, and ferroptosis. Small-molecule inhibitors of LPCAT3 have
not yet been described and would offer complementary tools to genetic
models of LPCAT3 loss, which causes neonatal lethality in mice. Here,
we report the discovery by high-throughput screening of a class of
potent, selective, and cell-active inhibitors of LPCAT3. We provide
evidence that these compounds inhibit LPCAT3 in a biphasic manner,
possibly reflecting differential activity at each subunit of the LPCAT3
homodimer. LPCAT3 inhibitors cause rapid rewiring of polyunsaturated
phospholipids in human cells that mirrors the changes observed in LPCAT3-null cells. Notably, these changes include not only
the suppression of C20:4 phospholipids but also corresponding increases
in C22:4 phospholipids, providing a potential mechanistic explanation
for the partial but incomplete protection from ferroptosis observed
in cells with pharmacological or genetic disruption of LPCAT3.

LPCAT3是参与兰兹循环（Lands cycle）的整合膜酰基转移酶，负责合成C20:4磷脂，并已被证实与肠道脂质吸收、脂蛋白组装及铁死亡（ferroptosis）等关键生物学过程密切相关。目前尚未见LPCAT3小分子抑制剂的相关报道，而此类抑制剂可作为LPCAT3缺失遗传模型的互补研究工具——LPCAT3缺失会导致小鼠出现新生期致死表型。本研究通过高通量筛选，发现了一类强效、高选择性且具有细胞活性的LPCAT3抑制剂。本研究证实，此类化合物以双相动力学方式抑制LPCAT3活性，这可能反映了LPCAT3同源二聚体每个亚基所具有的不同调控特性。LPCAT3抑制剂可快速重塑人细胞内的多不饱和磷脂谱，其变化模式与LPCAT3基因敲除细胞中观察到的结果一致。值得注意的是，这些变化不仅包括C20:4磷脂的水平下调，还伴随C22:4磷脂的相应上调，这为"采用药物或遗传学手段干扰LPCAT3后，细胞仅能获得部分而非完全的铁死亡保护"这一现象提供了潜在的机理解释。