The reported progressive decline in hepatic XBP1 post-transcriptional splicing has been mainly attributed to an increase in IRE1α S-nitrosylation and depleted endoribonuclease activity mediated by elevated inducible nitric oxide synthase (iNOS) activity, during metaflammation characteristic of metabolic syndrome and obesity (76). Here, ERN1 is linked to obesity due to melanocortin 4 receptor deficiency.