SMAD3 and neoplasm: By analyzing the RNA‐seq data and through multiple fundamental experiments, we confirmed HOOK1 inhibited the TGF‐β/ALK5/p‐Smad3 canonical signaling pathway and the noncanonical TGF‐β/MEK/ERK/c‐Myc signal, which contributed to suppress the tumor growth and metastasis in ccRCC.