Here we show that TLY012 induces DR-mediated apoptosis in α-SMA+ MFBs through upregulated DR5 and reverses established skin fibrosis in scleroderma by targeting α-SMA+DR+ MFBs differentiated from dermal fibroblasts, the predominant profibrogenic cell population in skin fibrosis. Here, ACTA1 is linked to scleroderma.