More recently, literature has shown that the IRE1α can respond directly to lipotoxicity through various means: (a) Under the environment of lipotoxic‐induced ER stress, IRE1α branch was activated by detecting unfolded proteins and chaperones via the IRE1α luminal domain; (b)Under the condition of lipid metabolism disorder, IRE1α‐sensed membrane lipid saturation via its transmembrane domain and was activated directly.36, 37, 38, 39. The gene discussed is ERN1; the disease is Disorder of lipid metabolism.