Endoplasmic reticulum stress aggravates ferroptosis via PERK/ATF4/HSPA5 pathway in UUO-induced renal fibrosis
Renal fibrosis, resulting from the transformation of damaged tubular epithelial cells (TECs), serves as a prevalent pathological condition observed in nearly all forms of advancing chronic kidney disease (CKD). Although crucial in fibrotic diseases, the association between endoplasmic reticulum stre...
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Frontiers Media S.A.
2025-04-01
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| author | Zhigang Huang Lihua Zhou Bin Liu Xiaoju Li Yu Sang |
| author_facet | Zhigang Huang Lihua Zhou Bin Liu Xiaoju Li Yu Sang |
| author_sort | Zhigang Huang |
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| description | Renal fibrosis, resulting from the transformation of damaged tubular epithelial cells (TECs), serves as a prevalent pathological condition observed in nearly all forms of advancing chronic kidney disease (CKD). Although crucial in fibrotic diseases, the association between endoplasmic reticulum stress (ERS) and ferroptosis remains incompletely elucidated. Herein, increased levels of heat shock protein family A member 5 (HSPA5), acting as a co-molecular in ERS and ferroptosis, along with EMT-associated alterations, including increased α-smooth muscle actin (α-SMA) and Col1a1 levels and decreased E-cad expression, were observed in fibrotic kidneys of Unilateral Ureteral Obstruction (UUO)-induced mouse models and TGF-β-induced EMT in HK-2 cells. The employment of ferrostatin-1 (Fer-1) improved these alterations and reversed TGF-β-induced EMT in vitro. More importantly, Inhibiting ERS by Tauroursodeoxycholate (TUDCA) reversed the alterations of ferroptosis, including GPX4 expression, reactive oxygen species (ROS) accumulation, iron overload, increased lipid peroxidation production, as well as EMT progression in vivo and in vitro. Whereas the overexpression of HSPA5 strikingly attenuated the inhibitory effects of TUDCA on ferroptosis and TGF-β-induced EMT in vitro. Mechanistically, Co-immunoprecipitation (Co-IP) tests showed that ATF4 engaged with and SUMOylated HSPA5 to trigger the HSPA5 signaling pathway in response to TGF-β. These findings illuminate that focusing on HSPA5 may present a promising therapeutic approach to enhance tubular epithelial cells’ survival and alleviate the progression of CKD. |
| format | Article |
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| publishDate | 2025-04-01 |
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| spelling | doaj-art-e4a970fa88284c40a6b3de78d764316c2025-08-20T01:51:53ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-04-011610.3389/fphar.2025.15459721545972Endoplasmic reticulum stress aggravates ferroptosis via PERK/ATF4/HSPA5 pathway in UUO-induced renal fibrosisZhigang Huang0Lihua Zhou1Bin Liu2Xiaoju Li3Yu Sang4Department of Urology, The First Affiliated Hospital of Yangtze University, Jingzhou, ChinaHubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan Hubei, ChinaDepartment of Urology, The First Affiliated Hospital of Yangtze University, Jingzhou, ChinaDepartment of Urology, The First Affiliated Hospital of Yangtze University, Jingzhou, ChinaDepartment of Urology, The First Affiliated Hospital of Yangtze University, Jingzhou, ChinaRenal fibrosis, resulting from the transformation of damaged tubular epithelial cells (TECs), serves as a prevalent pathological condition observed in nearly all forms of advancing chronic kidney disease (CKD). Although crucial in fibrotic diseases, the association between endoplasmic reticulum stress (ERS) and ferroptosis remains incompletely elucidated. Herein, increased levels of heat shock protein family A member 5 (HSPA5), acting as a co-molecular in ERS and ferroptosis, along with EMT-associated alterations, including increased α-smooth muscle actin (α-SMA) and Col1a1 levels and decreased E-cad expression, were observed in fibrotic kidneys of Unilateral Ureteral Obstruction (UUO)-induced mouse models and TGF-β-induced EMT in HK-2 cells. The employment of ferrostatin-1 (Fer-1) improved these alterations and reversed TGF-β-induced EMT in vitro. More importantly, Inhibiting ERS by Tauroursodeoxycholate (TUDCA) reversed the alterations of ferroptosis, including GPX4 expression, reactive oxygen species (ROS) accumulation, iron overload, increased lipid peroxidation production, as well as EMT progression in vivo and in vitro. Whereas the overexpression of HSPA5 strikingly attenuated the inhibitory effects of TUDCA on ferroptosis and TGF-β-induced EMT in vitro. Mechanistically, Co-immunoprecipitation (Co-IP) tests showed that ATF4 engaged with and SUMOylated HSPA5 to trigger the HSPA5 signaling pathway in response to TGF-β. These findings illuminate that focusing on HSPA5 may present a promising therapeutic approach to enhance tubular epithelial cells’ survival and alleviate the progression of CKD.https://www.frontiersin.org/articles/10.3389/fphar.2025.1545972/fullHSPA5ferroptosisendoplasmic reticulum stressepithelial-tomesenchymal transitionrenal fibrosis |
| spellingShingle | Zhigang Huang Lihua Zhou Bin Liu Xiaoju Li Yu Sang Endoplasmic reticulum stress aggravates ferroptosis via PERK/ATF4/HSPA5 pathway in UUO-induced renal fibrosis Frontiers in Pharmacology HSPA5 ferroptosis endoplasmic reticulum stress epithelial-tomesenchymal transition renal fibrosis |
| title | Endoplasmic reticulum stress aggravates ferroptosis via PERK/ATF4/HSPA5 pathway in UUO-induced renal fibrosis |
| title_full | Endoplasmic reticulum stress aggravates ferroptosis via PERK/ATF4/HSPA5 pathway in UUO-induced renal fibrosis |
| title_fullStr | Endoplasmic reticulum stress aggravates ferroptosis via PERK/ATF4/HSPA5 pathway in UUO-induced renal fibrosis |
| title_full_unstemmed | Endoplasmic reticulum stress aggravates ferroptosis via PERK/ATF4/HSPA5 pathway in UUO-induced renal fibrosis |
| title_short | Endoplasmic reticulum stress aggravates ferroptosis via PERK/ATF4/HSPA5 pathway in UUO-induced renal fibrosis |
| title_sort | endoplasmic reticulum stress aggravates ferroptosis via perk atf4 hspa5 pathway in uuo induced renal fibrosis |
| topic | HSPA5 ferroptosis endoplasmic reticulum stress epithelial-tomesenchymal transition renal fibrosis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1545972/full |
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