Loss of Beclin 1 Primes Colorectal Cancer Cells for Immunogenic Necroptosis via Transcriptional De-Repression of RIPK1/RIPK3/MLKL Axis

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Abstract

Background Colorectal cancer (CRC) frequently develops resistance to apoptotic cues, creating a clinical imperative to explore alternative forms of programmed cell death. Necroptosis, a regulated form of necrosis driven by RIPK1, RIPK3, and MLKL, is increasingly recognised for its immunogenic potential, yet the transcriptional control of this pathway remains poorly understood. Here, we identify Beclin 1, a canonical autophagy regulator, as a key transcriptional suppressor of necroptotic programming. Methods and Results Using siRNA-mediated knockdown in HT-29 colorectal cancer cells, we observed a significant reduction in Beclin 1 protein levels, accompanied by a 2.4–2.9-fold upregulation of RIPK1, RIPK3, and MLKL transcripts. Western blot analysis revealed modest increases in phosphorylated RIPK1 and MLKL, indicating functional sensitisation to necroptotic death without full pathway execution. Conclusions These findings suggest that Beclin 1 maintains cellular survival not solely through autophagy but also by repressing necroptosis at the transcriptional level. Its loss reconfigures CRC cell fate, predisposing them to inflammatory, caspase-independent death. Targeting Beclin 1 may therefore expose a previously unrecognised vulnerability in apoptosis-resistant CRC, opening new avenues for necroptosis-based immunotherapeutic interventions.

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