Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression

Multiple myeloma (MM), the world’s second most common hematologic malignancy, poses considerable clinical challenges due to its aggressive progression and resistance to therapy. Addressing these challenges requires a detailed understanding of the mechanisms driving MM initiation, progression, and therapeutic resistance. This study identifies the pseudokinase tribble homolog 3 (TRIB3) as a high-risk factor that promotes MM malignancy in vitro and in vivo. Mechanistically, TRIB3 directly interacts with structure-specific recognition protein 1 (SSRP1) and ubiquitin-specific peptidase 10 (USP10), facilitating the formation of a TRIB3/USP10/SSRP1 ternary complex. This complex stabilizes SSRP1 via USP10-mediated deubiquitination, thereby driving MM cell proliferation. Furthermore, a stapled peptide, SP-A, was developed, which effectively disrupts the TRIB3/USP10/SSRP1 complex, leading to a decrease in SSRP1 levels by inhibiting its stabilization through USP10. Notably, SP-A exhibits strong synergistic effects when combined with the proteasome inhibitor bortezomib. Given the critical role of the TRIB3/USP10/SSRP1 complex in MM pathophysiology, it represents a promising therapeutic target for MM treatment.