The NADPH–autophagy rheostat: Reprogramming pentose phosphate flux to prevent lysosomal membrane permeabilization and chemo-induced senescence

Explore mammalian analogs of yeast Stb5 (e.g., NRF2, MondoA/ChREBP, ATF4) and mitochondrial SIRT3 to modulate NADPH supply via pentose phosphate pathway flux and mitochondrial sources. Using bleomycin-induced ROS models, combine genetic and pharmacologic modulation of PPP (e.g., G6PD overexpression, 6-AN inhibition), SIRT3 activators, and CMA enhancers to test if boosting NADPH stabilizes lysosomal membranes, maintains autophagic flux, and reduces senescence-associated secretory phenotype (SASP). This targeted redox-autophagy setpoint approach aims to prevent lysosomal membrane permeabilization and chemo-induced senescence, potentially reducing off-target fibrosis and neurotoxicity while preserving antitumor efficacy.

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