Fibroblast　activation　promotes　remodeling　of　the　extracellular　matrix　(ECM),　and　the　fibrotic　remodeling　ECM　further　stimulating　fibroblast　activation　and　advancing　pulmonary　fibrosis　(PF).　syndecan-4　(SDC4)　is　the　key　mediator　of　ECM-cell　signaling,　but　its　action　in　PF　remains　unclear.　Using　decellularized　lung　ECM　(dECM),　this　study　found　that　fibrotic　ECM　enhanced　fibroblast　activation　via　SDC4-regulated　integrin-αvβ1　expression　and　activation,　and　FAK/AKT　phosphorylation.　Meanwhile,　SDC4　knockdown　inhibited　fibrotic　ECM-induced　TGF-β1　synthesis　and　PKCα　activation.　A　Duolink-proximity　ligation　assay　confirmed　extracellular　interactions　between　SDC4　and　integrin-αvβ1,　and　the　SDC4　blocking　antibody　Anti-SDC4(93-121)　prevented　this　interaction,　resulting　in　an　effect　consistent　with　knockdown　of　SDC4.　The　interfering　peptide　SDC487-131　diminished　the　interaction　between　SDC4　and　integrin-αvβ1,　subsequently　inhibited　the　activation　of　FAK/AKT,　Smad2/3　and　PKCα/NF-κB　pathways　and　exhibited　anti-PF　activity　comparable　to　that　of　SDC4　knockdown　and　Anti-SDC4(93-121).　A　docking　mode　of　SDC487-131　with　the　Calf-1/Calf-2　domain　of　integrin-αv　was　constructed　by　using　the　AlphaFold2-Multimer　model,　and　peptide　design　was　performed　to　obtain　a　novel　polypeptide　chain　CS-9　with　enhanced　anti-PF　effect.　This　study　found　that　the　biomaterial,　lung　ECM,　regulates　fibroblast　activation　through　the　collaboration　of　SDC4　and　integrin-αvβ1,　and　obtained　a　novel　SDC487-131-derived　peptide　that　may　prevent　fibrotic　ECM　from　promoting　PF.　©　2025　The　Author(s).　Published　by　Oxford　University　Press.