Mitocurcumin mediated redox disruption and metabolic rewiring induces tumor regression in Drosophila intestinal stem cell tumors

Authors

Diwate, S., Chowdhury, U., Gadewal, N., Jadhav, S., Gota, V., Khadilkar, R. J.

Abstract

Mitochondria-targeted modulation of redox homeostasis has emerged as a promising strategy for controlling pathological cell proliferation. Here, we investigate the effects of Mitocurcumin in a Yorkie-driven intestinal stem cell tumor model in Drosophila. Using an integrative, genetically tractable approach combining in silico molecular modelling with in vivo functional analyses, we identify thioredoxin reductase (TrxR) as a conserved redox-associated target of Mitocurcumin. Docking and molecular dynamics simulations predict a stable interaction of Mitocurcumin with both Drosophila and mammalian TrxR homologs. Functionally, Mitocurcumin treatment reduces mitotic activity, elevates reactive oxygen species (ROS) selectively within escargot-positive intestinal stem cell population, enhances apoptosis in the tumor-bearing guts, and causes significant mitochondrial membrane depolarization. These cellular effects coincide with dose-dependent regression of Yorkie-induced intestinal hyperplasia. Despite mitochondrial functional impairment, mitochondrial morphology remains largely preserved, suggesting primary disruption of redox buffering rather than structural collapse. Metabolomic profiling of these guts further reveals remodelling of energy metabolism consistent with adaptive responses to oxidative stress. Importantly, Mitocurcumin alleviates tumor-associated organismal bloating and significantly extends lifespan indicating a previously uncharacterized systemic, organism-wide response to Mitocurcumin treatment in an in vivo scenario. Collectively, our findings establish TrxR-mediated redox regulation as a critical vulnerability in Yorkie-driven hyperproliferation and highlight the utility of Drosophila as an integrative in vivo platform for evaluating mitochondria-targeted bioactive molecules.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 29 Aug 2026.

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