Endoplasmic reticulum membrane-associated E3 ubiquitin ligase that plays a critical role in mitigating endoplasmic reticulum stress, the regulation of cholesterol and lipid homeostasis, and ferroptosis (PubMed:25088257, PubMed:35941365, PubMed:39216628). Acts as a pivotal component of both the Ac/N-degron pathway (targeting the N-terminal acetyl group of substrates) and the ER-associated protein degradation- cytosol (ERAD-C) pathway (targeting misfolded substrates) (PubMed:30425097, PubMed:35941365). For instance, mediates the degradation of Ac/N-degron-bearing proteins such as the G protein regulator RGS2 and the lipid droplet protein PLIN2 (PubMed:39216628). Suppresses endoplasmic reticulum stress and ferroptosis through cytosolic POMC degradation (By similarity). Prevents ferroptosis by acting as a NADPH sensor during lipid peroxidation through its C- terminal regulatory region (PubMed:35941365). Facilitates also the degradation of selected endoplasmic reticulum proteins by associating with signal peptide peptidase for the turnover of endogenous tail- anchored proteins (PubMed:29519897). Promotes ubiquitination of DIO2, leading to its degradation (PubMed:19651899). By ubiquitinating and thereby modulating the stability of many proteins of the cholesterol pathway including SQLE, CYP51A1, CYP11A1 and HMGCR, acts as a crucial post-translational regulator of cholesterol synthesis (PubMed:24449766, PubMed:31904814, PubMed:36958722). {ECO:0000250|UniProtKB:Q6ZQ89, ECO:0000269|PubMed:15673284, ECO:0000269|PubMed:19651899, ECO:0000269|PubMed:24449766, ECO:0000269|PubMed:25088257, ECO:0000269|PubMed:29519897, ECO:0000269|PubMed:30425097, ECO:0000269|PubMed:31904814, ECO:0000269|PubMed:35941365, ECO:0000269|PubMed:36958722, ECO:0000269|PubMed:39216628}. This is the function of ENSG00000145495 (MARCHF6, membrane associated ring-CH-type finger 6).