TGFB1 and infection: These findings establish SB431542 as a promising broad-spectrum coronavirus inhibitor with a unique triple-mechanism approach that simultaneously targets viral entry via TGF-β/Smad modulation, disrupts ORF3a-mediated lysosomal dysfunction affecting assembly, and attenuates TGF-β-induced apoptosis during late-stage infection, collectively imposing multiple selective constraints that impede escape mutation development.