In vitro, hypoxic stress increased the expressions of HADC6, TGF‐β1, TGF‐βR1, Nkx‐2.5 and collagen I and III proteins or/and genes in CFs but not in H9C2; these alterations were significantly prevented by the HADC6 silencing and TubA loading, providing evidence and a mechanistic explanation for the participation of HADC6 mediated TGF‐β1/TGF‐βR1‐Smad2/3/Nkx‐2.5 and ‐Erk1/2 signalling in cardiac fibrosis and dysfunction in post‐MI mice. The gene discussed is DNMBP; the disease is myocardial infarction.