AF induced prominent mucus production versus other fungi and control. Weaker mucus production by PN extract versus CA, AA and controlOne hundred and eighty five genes specifically upregulated by AF but not PN or AAEGFR and TGF‐α inhibitor markedly reduced MUC5AC expression in AF‐exposed cells. MMP inhibitor or TACE inhibitor lowered level of MUC5AC mRNA versus control. MUC5AC mRNA was also suppressed by TACE siRNA versus controlThe robust serine protease activity of AF was essential for mucin synthesis and expression of MUC5AC in AECs via activation of TACE/TGF‐α/EGFR pathway. Here, ADAM17 is linked to atrial fibrillation.