Dastghaib Sanaz, Shafiee Sayed Mohammad, Ramezani Fatemeh, Ashtari Niloufar, Tabasi Farhad, Saffari-Chaleshtori Javad, Siri Morvarid, Vakili Omid, Igder Somayeh, Zamani Mozhdeh, Niknam Maryam, Nasery Mahshid Moballegh, Kokabi Fariba, Wiechec Emilia, Mostafavi-Pour Zohreh, Mokarram Pooneh, Ghavami Saeid
Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, 7193635899, Shiraz, Iran.
Autophagy Research Center, Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran.
Eur J Pharmacol. 2025 Feb 5;988:177210. doi: 10.1016/j.ejphar.2024.177210. Epub 2024 Dec 18.
The development of chemo-resistance remains a significant hurdle in effective cancer therapy. NRF1 and NRF2, key regulators of redox homeostasis, play crucial roles in the cellular response to oxidative stress, with implications for both tumor growth and resistance to chemotherapy. This study delves into the dualistic role of NRF2, exploring its protective functions in normal cells and its paradoxical support of tumor survival and drug resistance in cancerous cells. We investigate the interplay between the PERK/NRF signaling pathway, ER stress, autophagy, and the unfolded protein response, offering a mechanistic perspective on how these processes contribute to chemoresistance. Our findings suggest that targeting NRF signaling pathways may offer new avenues for overcoming resistance to chemotherapeutic agents, highlighting the importance of a nuanced approach to redox regulation in cancer treatment. This research provides a molecular basis for the development of NRF-targeted therapies, potentially enhancing the efficacy of existing cancer treatments and offering hope for more effective management of resistant tumors.
化疗耐药性的发展仍然是有效癌症治疗中的一个重大障碍。NRF1和NRF2作为氧化还原稳态的关键调节因子，在细胞对氧化应激的反应中发挥着至关重要的作用，对肿瘤生长和化疗耐药性均有影响。本研究深入探讨了NRF2的双重作用，探究其在正常细胞中的保护功能以及在癌细胞中对肿瘤存活和耐药性的矛盾支持。我们研究了PERK/NRF信号通路、内质网应激、自噬和未折叠蛋白反应之间的相互作用，从机制角度阐述了这些过程如何导致化疗耐药性。我们的研究结果表明，靶向NRF信号通路可能为克服对化疗药物的耐药性提供新途径，凸显了在癌症治疗中采用细致入微的氧化还原调节方法的重要性。这项研究为开发靶向NRF的疗法提供了分子基础，有望提高现有癌症治疗的疗效，并为更有效地管理耐药肿瘤带来希望。
