Background Follicular atresia,a complex degenerative process regulated by multiple molecular mechanisms,significantly affects female reproductive performance in animals.While granulosa cell(GC)apoptosis has been well ...Background Follicular atresia,a complex degenerative process regulated by multiple molecular mechanisms,significantly affects female reproductive performance in animals.While granulosa cell(GC)apoptosis has been well established as a primary mechanism underlying follicular atresia,the potential involvement of ferroptosis,which is an irondependent form of regulated cell death,remains largely unexplored in chickens.Results Using a tamoxifen(TMX)-induced avian model of follicular atresia,we demonstrated that ferroptosis plays a critical role in follicular degeneration.Inhibition of ferroptosis through pharmacological agents significantly restored follicular function,underscoring its potential as a therapeutic target.Notably,we observed a significant upregulation of ubiquitin-specific peptidase 9,X-linked(USP9X)in GCs during atresia.Through comprehensive in vitro and in vivo investigations,we confirmed that USP9X facilitates follicular atresia by promoting ferroptosis in GCs.Mechanistically,USP9X induces ferroptosis by stabilizing Beclin1 through deubiquitination,thereby activating autophagy-dependent ferroptosis.This pathway was effectively suppressed by autophagy inhibitors,emphasizing the essential role of autophagy in USP9X-mediated ferroptosis.Conclusions Our findings provide the evidence that the USP9X-Beclin1 axis regulates autophagy-dependent ferroptosis during avian follicular atresia.These insights reveal novel molecular targets and potential genetic markers for improving reproductive efficiency in chicken breeding programs.展开更多
自噬是维持细胞存活、分化、生长和稳态所必须的一种溶酶体降解途径(Levine and Kroemer,2008)。最近的大量研究证实自噬与多种肿瘤细胞的恶性转化和肿瘤细胞的生长有关。哺乳动物雷帕霉素靶蛋白(m TOR)和自噬相关基因Beclin1与细胞自...自噬是维持细胞存活、分化、生长和稳态所必须的一种溶酶体降解途径(Levine and Kroemer,2008)。最近的大量研究证实自噬与多种肿瘤细胞的恶性转化和肿瘤细胞的生长有关。哺乳动物雷帕霉素靶蛋白(m TOR)和自噬相关基因Beclin1与细胞自噬关系密切,其可通过调节细胞自噬活性而在肿瘤的发生发展过程中发挥重要的作用。目前,有关肿瘤细胞自噬性死亡的研究受到越来越多人的关注,它很可能成为肿瘤治疗的新靶点。因此,深入研究m TOR、Beclin1在调控自噬过程中与肿瘤的发生发展关系可能对临床上有关肿瘤治疗方面的研究有重要意义。本文现就对自噬通路中m TOR、Beclin1与肿瘤关系的研究进展作一简要概述。展开更多
基金funded by The National Key Research and Development Program of China,grant number 2022YFF1000202Sichuan Science and Technology Program,grant number 2023NSFSC1940,2021YFYZ0007 and 2024YFNH0025+1 种基金National Natural Science Foundation of China Grants,grant number 32402745China Agriculture Research System of MOF and MARA,grant number CARS-40。
文摘Background Follicular atresia,a complex degenerative process regulated by multiple molecular mechanisms,significantly affects female reproductive performance in animals.While granulosa cell(GC)apoptosis has been well established as a primary mechanism underlying follicular atresia,the potential involvement of ferroptosis,which is an irondependent form of regulated cell death,remains largely unexplored in chickens.Results Using a tamoxifen(TMX)-induced avian model of follicular atresia,we demonstrated that ferroptosis plays a critical role in follicular degeneration.Inhibition of ferroptosis through pharmacological agents significantly restored follicular function,underscoring its potential as a therapeutic target.Notably,we observed a significant upregulation of ubiquitin-specific peptidase 9,X-linked(USP9X)in GCs during atresia.Through comprehensive in vitro and in vivo investigations,we confirmed that USP9X facilitates follicular atresia by promoting ferroptosis in GCs.Mechanistically,USP9X induces ferroptosis by stabilizing Beclin1 through deubiquitination,thereby activating autophagy-dependent ferroptosis.This pathway was effectively suppressed by autophagy inhibitors,emphasizing the essential role of autophagy in USP9X-mediated ferroptosis.Conclusions Our findings provide the evidence that the USP9X-Beclin1 axis regulates autophagy-dependent ferroptosis during avian follicular atresia.These insights reveal novel molecular targets and potential genetic markers for improving reproductive efficiency in chicken breeding programs.
