Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers an unfolded protein response (UPR) for stress adaptation, the failure of which induces cell apoptosis and tissue/organ damage. The molecular switches underlying how the UPR selects for stress adaptation over apoptosis remain unknown. Here, we discovered that accumulation of unfolded/misfolded proteins selectively induces N 6-adenosine-methyltransferase-14 (METTL14) expression. METTL14 promotes C/EBP-homologous protein (CHOP) mRNA decay through its 3′ UTR N 6-methyladenosine (m6A) to inhibit its downstream pro-apoptotic target gene expression. UPR induces METTL14 expression by competing against the HRD1-ER-associated degradation (ERAD) machinery to block METTL14 ubiquitination and degradation. Therefore, mice with liver-specific METTL14 deletion are highly susceptible to both acute pharmacological and alpha-1 antitrypsin (AAT) deficiency-induced ER proteotoxic stress and liver injury. Further hepatic CHOP deletion protects METTL14 knockout mice from ER-stress-induced liver damage. Our study reveals a crosstalk between ER stress and mRNA m6A modification pathways, termed the ERm6A pathway, for ER stress adaptation to proteotoxicity. [Display omitted] • UPR selectively induces m6A writer METTL14 protein expression • METTL14 suppresses CHOP-induced apoptosis for ER stress adaptation • HRD1 is a METTL14 ubiquitin ligase and UPR suppresses HRD1-mediated METTL14 degradation • CHOP suppression rescues METTL14 null mice from proteotoxic liver damage ERAD is critical for ER-stress adaptation, and its failure triggers cell apoptosis. Wei et al. discovered that ER stress induces N 6-adenosine-methyltransferase METTL14 expression by suppressing HRD1-mediated ubiquitination to promote CHOP mRNA decay for inhibiting CHOP-induced apoptosis. This study defines an ERm6A pathway, underlying how ERAD selects stress adaptation over apoptosis. [ABSTRACT FROM AUTHOR]