Inhibition of SDE2 promotes autophagy-dependent ferroptosis in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is an incurable plasma cell malignancy with high relapse rate. Recent studies have implicated dysregulated autophagy and ferroptosis in MM progression; however, the molecular links remain elusive. This study investigated the role of SDE2, a ubiquitin-like protein overexpressed in MM, in modulating autophagy-ferroptosis crosstalk via ATG5 degradation with the aim of identifying novel therapeutic targets. METHODS: Using bioinformatic analysis of TCGA data, we identified SDE2 as a prognostic marker in MM. Functional validation included Western blot, co-immunoprecipitation, and ubiquitination assays in MM cell lines (H929, RPMI8226, OPM-2, and KMS-11) and patient-derived samples. Transwell migration, soft agar colony formation, and flow cytometry were used to assess cellular phenotypes. In vivo efficacy was tested using xenograft models. RESULTS: SDE2 overexpression correlates with poor MM prognosis and promotes tumor cell survival, migration, and proliferation. Mechanistically, SDE2 binds to ATG5, facilitating K48-linked ubiquitination and proteasomal degradation, thereby suppressing autophagy and ferroptosis. Knockdown of SDE2 restored ATG5 levels, reactivated autophagy, and sensitized MM cells to ferroptosis. Combined SDE2 silencing and pharmacological ATG5/7 activation (Antitumor agent-82) synergistically suppressed tumor growth in vitro and in vivo. CONCLUSION: The SDE2-ATG5 axis serves as a critical regulator of the autophagy-ferroptosis crosstalk in MM. Targeting SDE2 restores ATG5-dependent autophagy, activates ferroptosis, and inhibits tumor growth. These findings suggest a novel therapeutic strategy that combines SDE2 inhibitors with autophagy agonists, potentially offering clinical benefits in MM treatment. This study provides further insight into autophagy-dependent ferroptosis in other malignancies.