Wenzhe Kong,Xudong Ding,Zhaoyu Wang,Lu Lu,Saijun Fan
As a common side effect of radiotherapy, radiation-induced intestinal injury (RIII) greatly affects the prognosis of patients and the efficacy of radiotherapy. Current therapeutic strategies for RIII are still very limited. Thus, the identification of effective radioprotective agents is of great importance. NVP-AUY922 is an HSP90 inhibitor with favorable anti-inflammatory and antioxidant activities. It has been proven to mitigate radiation-induced lung injury. However, its effects on the alleviation of RIII remain unclear. In this study, our data indicated that NVP-AUY922 remarkably increased the survival rate after radiation exposure. NVP-AUY922 treatment could enhance the viability of intestinal stem cells (ISCs) and promote the recovery of the small intestine. In addition, it also inhibited intestinal inflammation and reshaped the gut microbiota structure. We found that the radioprotective effect of NVP-AUY922 is partially dependent on EPHX1. In addition, NVP-AUY922 could attenuate dextran sulfate sodium (DSS)-induced colitis and promote intestinal barrier recovery. Thus, our results suggest that NVP-AUY922 contributes to the amelioration of intestinal injury after radiation exposure, which offers a new approach for the prevention of RIII.
Non-small cell lung cancer (NSCLC) treatment is often compromised by acquired resistance and, in the context of photothermal therapy (PTT), by tumor thermotolerance─a protective stress response mediated by the molecular chaperone heat shock protein 90 (HSP90). To address this dual challenge, we developed a multifunctional nanoplatform (Cu9S8@Lum NPs) that synergistically integrates NIR-II PTT with HSP90 inhibition. This nanosystem is based on a Cu9S8 nanocore with high photothermal conversion efficiency, loaded with the HSP90 inhibitor Luminespib and designed for pH-responsive drug release. This spatiotemporally coordinated strategy enables concurrent tumor hyperthermia and molecular interference with the heat-shock defense mechanism. In vitro, the nanoparticles effectively suppressed HSP90 expression, exacerbated cellular oxidative stress, and induced mitochondrial apoptosis, resulting in markedly enhanced cytotoxicity compared to PTT alone. In vivo, the nanoplatform demonstrated effective tumor accumulation and, under mild NIR-II irradiation, achieved significant tumor growth inhibition in a syngeneic model. This work presents a mechanism-informed nanomaterial strategy to overcome thermotolerance in NSCLC, advancing the development of synergistic cancer nanotherapeutics.
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