Study elucidates mechanism connecting ER membrane remodeling to pyroptosis in cancer cells

Pyroptosis, a highly inflammatory type of programmed cell death, has garnered attention for its potential in cancer treatment. Characterized by cell swelling and the formation of "bubble" structures, pyroptosis is closely linked to the dynamics of the endoplasmic reticulum (ER). Despite growing interest, the precise mechanisms by which the ER triggers pyroptosis remain poorly understood, and the development of effective small molecules to induce this form of cell death has been limited. Given the importance of this process in cancer progression, understanding ER-associated pyroptosis has become a critical area of research.

In a study (DOI: 10.1093/procel/pwae049) published on September 10, 2024, in Protein & Cell, researchers from Peking University and Peking University People's Hospital elucidated a novel mechanism connecting ER membrane remodeling to pyroptosis. Their findings reveal that by targeting reticulon-4 (RTN4), a key regulator of ER membrane curvature, it is possible to induce pyroptosis in cancer cells and promote antitumor immunity.

The researchers used a biotin-labeled chemical probe, α-mangostin (α-MG), to identify RTN4 as a crucial player in ER membrane curvature regulation. α-MG induces RTN4 degradation through the ubiquitin-proteasome system by recruiting the E3 ligase UBR5, triggering extensive ER remodeling. This degradation results in a shift in ER morphology from tubules to sheets, facilitating ER fusion with the plasma membrane and the formation of the typical "bubble" structures of pyroptotic cells.

Further investigation revealed that RTN4 deficiency activates the caspase-3/GSDME pathway, driving pyroptosis. In vivo studies demonstrated that RTN4 knockdown significantly inhibited tumor growth and enhanced immune responses, particularly when combined with anti-PD-1 therapy. The study also highlighted α-MG as a potential small molecule degrader of RTN4, underscoring its therapeutic potential in cancer treatment.

Dr. Ke-Wu Zeng, one of the study's corresponding authors, emphasized the transformative nature of these findings: Our research identifies RTN4 as a critical regulator of pyroptosis through its role in ER membrane dynamics. Targeting RTN4 can induce a potent antitumor immune response, offering a prospective strategy for anticancer immunotherapy.

The discovery of RTN4 as a druggable target for pyroptosis opens new possibilities for cancer treatment. Small molecules such as α-MG, which degrade RTN4, could be developed into novel anticancer agents. Furthermore, the synergistic effect of RTN4 degradation with immune checkpoint inhibitors like anti-PD-1 therapy highlights the potential for combination therapies to improve antitumor efficacy. This research lays the foundation for future clinical applications targeting ER dynamics to combat cancer.