Inhibition of SDE2 promotes autophagy-dependent ferroptosis in multiple myeloma

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.

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.

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.

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.