LACTB, or serine beta-lactamase-like protein, is the only mammalian mitochondrial homolog evolved from penicillin-binding proteins and β-lactamases in bacteria. As an active-site serine protease, it polymerizes into stable filaments located in the mitochondrial intermembrane space, modulating mitochondrial lipid metabolism and involved in submitochondrial organization. It is also associated with multiple biological processes such as ferroptosis, which is an emerging cancer defense mechanism, and is implicated in various diseases, especially cancers [3,4].

In liver cancer, LACTB knockout promotes cell viability, colony formation, and tumour growth, while its overexpression inhibits these processes by regulating ferroptosis. Specifically, LACTB blocks HSPA8 transcription in a p53-dependent manner, leading to increased NCOA4-mediated ferritinophagy and inhibition of SLC7A11/GSH/GPX4 signalling, thus triggering ferroptosis and suppressing liver cancer progression [1]. In mice, LACTB deletion results in impaired glucose tolerance, elevated lipid levels, and increased sensitivity to kidney disease, while tubule-specific overexpression protects from kidney injury. LACTB acts as a mitochondrial protease to cleave and activate phospholipase A2 group VI (PLA2G6), and genetic deletion of PLA2G6 abolishes the protective function of LACTB. LACTB and downstream PLA2G6 regulate mitochondrial function and ferroptosis by converting oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine [2].

In conclusion, LACTB plays a crucial role in lipid metabolism, ferroptosis regulation, and mitochondrial function. Studies using gene knockout and overexpression mouse models have revealed its significance in liver cancer and kidney-metabolic disorders. These findings suggest LACTB could be a potential therapeutic target for related diseases.