Marchf6, an E3 ubiquitin ligase embedded in the endoplasmic reticulum membranes, is a crucial regulator in multiple biological processes. It participates in endoplasmic reticulum associated degradation, and many of its substrates are involved in sterol and lipid metabolism [3]. It also acts as an NADPH sensor, with its E3 ligase activity upregulated by the interaction with NADPH [1]. This regulation is linked to the control of ferroptosis, a form of cell death caused by excessive iron-dependent lipid peroxidation [1].

In Marchf6-deficient tumours, inhibiting ferroptosis rescued tumour growth, and Marchf6-/-mice showed peri-natal lethality, indicating that Marchf6 is essential for regulating ferroptosis in tumourigenesis and fetal development [1]. POMC-Cre-mediated Marchf6-deficient mice exhibited hyperphagia, reduced energy expenditure, and weight gain, suggesting that Marchf6 critically regulates endoplasmic reticulum stress, ferroptosis, and metabolic homeostasis in POMC neurons [2].

In conclusion, Marchf6 is a key regulator of ferroptosis and metabolic homeostasis. The gene knockout mouse models have revealed its significance in tumourigenesis, fetal development, and metabolic disorders, providing insights into understanding the mechanisms of these diseases and potential therapeutic targets.