TRIM48 is an E3 ubiquitin ligase that functions as a multifaceted regulator of oxidative stress responses and innate immunity. Mechanistically, TRIM48 promotes K48-linked polyubiquitination of protein methyltransferase PRMT1, targeting it for proteasomal degradation 1. This degradation relieves PRMT1's inhibitory effects on apoptosis signal-regulating kinase 1 (ASK1), a ROS-responsive kinase, thereby promoting ASK1 activation and oxidative stress-induced cell death 1. TRIM48 additionally suppresses PRMT1-mediated methylation of FOXO1, enhancing FOXO1 transcriptional activity 1. Beyond oxidative stress responses, TRIM48 functions as an inducible negative feedback regulator of RIG-I-mediated antiviral signaling, suppressing IRF3 and NF-κB activation and reducing interferon production in a ubiquitin ligase activity-dependent manner 2. Disease relevance is evident in glioblastoma, where TRIM48 is reduced and its overexpression inhibits cell growth via ERK1/2 pathway blockade 3. TRIM48 expression itself is tightly controlled by the FBXO22-containing SCF ubiquitin ligase complex 4. These findings establish TRIM48 as a critical hub integrating oxidative stress sensing with innate immune regulation, positioning it as a potential therapeutic target for cancer and oxidative stress-associated disorders.