RNF32 is a RING-H2 E3 ubiquitin ligase located on chromosome 7 that functions as a calcium-dependent signaling regulator with emerging roles in cancer pathogenesis. Structurally, RNF32 contains two RING-H2 domains separated by an IQ domain and is expressed primarily in testis and ovary during spermatogenesis 1, though its expression extends to intestinal stem cells 2. Mechanistically, RNF32 functions as a calmodulin-dependent E3 ligase that regulates NF-κB signaling in the intestinal epithelium. Elevated intracellular calcium triggers RNF32 binding to calmodulin, leading to RNF32 autoubiquitylation and NEMO recruitment to the IκB kinase complex, ultimately activating NF-κB signaling in response to bacterial lipopolysaccharides 2. RNF32 also undergoes calcium-induced phase separation, which facilitates NEMO condensate formation and IKK activation 2. In colorectal cancer, RNF32 emerges as a critical driver of metastasis. It catalyzes K48-linked ubiquitination of GSK3β at K60, stabilizing β-catenin and activating Wnt signaling, which upregulates CCL2 and recruits SPP1+ macrophages to remodel the metastatic niche 3. RNF32 promotes tumor cell proliferation, invasion, and epithelial-mesenchymal transition while enhancing cancer stemness 3. RNF32 appears in prognostic signatures for colon cancer 4 5, with elevated expression correlating with poor outcomes and reduced immunotherapy response. Indole-3-acetic acid has been identified as a potential RNF32 inhibitor for therapeutic intervention 3.