Having the tight correlation of IRHOM2 destabilization with catalytic function‐associated DHHC domain activity of ZDHHC3, to further confirm whether ZDHHC3 with C157A mutant in DHHC domain was required for the accelerated role of ZDHHC3 in the setting of NASH, we then subjected AAV‐TBG‐Zdhhc3, AAV‐TBG‐Zdhhc3 (C157A), or AAV‐TBG‐Blank to Zdhhc3‐HepKO mice, accompanied by 16‐weeks HFHC‐triggered NASH model in vivo (Figure S14a,b, Supporting Information). The gene discussed is RHBDF2; the disease is metabolic dysfunction-associated steatohepatitis.