Lpcat3, also known as lyso-phosphatidylcholine acyltransferase 3 and MBOAT5, is a key phospholipid remodeling enzyme. It is involved in the Lands' cycle, specifically catalyzing the incorporation of fatty acyl chains, especially polyunsaturated fatty acids (PUFAs), into the sn-2 site of phosphatidylcholine [3,4]. This function is crucial for maintaining systemic lipid homeostasis, influencing processes like lipid absorption in the intestine, lipoprotein secretion, and de novo lipogenesis in the liver [4]. Lpcat3 is also implicated in important biological processes such as cell death, particularly ferroptosis, and oncogenesis [3]. Genetic models, like gene knockout (KO) mouse models, can be valuable for studying Lpcat3 function as Lpcat3-null in mice causes neonatal lethality, highlighting its essential role [6].

In lung adenocarcinoma (LUAD), Lpcat3 levels are positively associated with ferroptosis sensitivity. Overexpression of Lpcat3 sensitizes LUAD cells to ferroptosis, while knockout shows the opposite effect. Zinc-finger E-box-binding (ZEB) protein directly binds the Lpcat3 promoter to stimulate its transcription in a Yes-associated protein (YAP)-dependent manner, with E1A-binding protein p300 (EP300) also involved in this transcriptional regulation [1]. In melanoma and lung cancer, mefloquine (Mef) upregulates Lpcat3 expression via activating IFN-γ-induced STAT1-IRF1 signaling, enhancing tumor ferroptosis and sensitizing cells to anti-PD-1 immunotherapy, and knockdown of Lpcat3 impairs this ferroptosis induction [2]. In rats with subarachnoid hemorrhage, suppressing Lpcat3 expression via shRNA improves oxidative stress, reduces brain edema, and alleviates behavioral and cognitive deficits, while upregulating it has opposing effects, indicating its role in early brain injury and ferroptosis [5].

In conclusion, Lpcat3 is essential for lipid metabolism and homeostasis. Through model-based research, it has been shown to play a significant role in ferroptosis-related disease conditions such as LUAD, melanoma, lung cancer, and subarachnoid hemorrhage-induced early brain injury. These findings provide potential therapeutic targets for these diseases by understanding Lpcat3's function in promoting or inhibiting ferroptosis and related biological processes.