Abstract
Relieving renal fibrosis are promising therapeutic strategies for chronic kidney disease (CKD). Here we showed that decreased homeobox A2 (HOXA2) expression with excessive ER stress activation were observed in the renal tissues of UUO mice established on male C57BL/6 mice and TGF-β1-induced human proximal tubular epithelial cells (HK-2 cells). After transfected HOXA2 overexpression plasmids into HK-2 cells and administered adeno-associated virus (AAV) containing HOXA2 to UUO mice, the expression of ER stress markers such as ATF6, GRP78 and CHOP decreased, renal dysfunction and fibrosis were significantly attenuated. Mechanistically, HOXA2 binds to the SIRT1 promoter, enhancing SIRT1 transcription and deacetylase activity, which led to ATF6 deacetylation and downregulation. The protective effect of HOXA2 was confirmed against the ER stress agonist thapsigargin. Moreover, DNMT1-mediated promoter methylation was identified as a potential mechanism for HOXA2 suppression in fibrosis. Targeting HOXA2 maybe an innovative therapeutic strategy for fibrosis treatment in CKD.
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The source data and the statistical data can be found in Supplementary Data 1 and Supplementary Materials and DNA-sequencing results can be found in NCBI database (SRA: PRJNA1377853). The data that support the findings of this study are available on request from the corresponding author.
References
Fountoulakis, N., Miyamoto, Y., Pavkov, M. E., Karalliedde, J. & Maltese, G. Pathophysiology of vascular ageing and the effect of novel cardio-renal protective medications in preventing progression of chronic kidney disease in people living with diabetes. Diabet. Med 42, e15464 (2025).
Bhayana, S., Schytz, P. A., Bisgaard Olesen, E. T., Soh, K. & Das, V. Single-Cell Advances in Investigating and Understanding Chronic Kidney Disease and Diabetic Kidney Disease. Am. J. Pathol. 195, 55–68 (2025).
Maeda, S. et al. MondoA and AKI and AKI-to-CKD Transition. J. Am. Soc. Nephrol. 35, 1164–1182 (2024).
Huang, R., Fu, P. & Ma, L. Kidney fibrosis: from mechanisms to therapeutic medicines. Signal Transduct. Target Ther. 8, 129 (2023).
Wang, Y. et al. Irisin ameliorates UUO-induced renal interstitial fibrosis through TGF-β1/periostin/MMP-2 signaling pathway. PLoS One 19, e0299389 (2024).
Hadpech, S. & Thongboonkerd, V. Epithelial-mesenchymal plasticity in kidney fibrosis. Genesis 62, e23529 (2024).
Jiang, W. et al. Eucommiae cortex extract alleviates renal fibrosis in CKD mice induced by adenine through the TGF-β1/Smad signaling pathway. J. Nat. Med 79, 170–179 (2025).
Cohen, C. et al. WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease. Nat. Commun. 15, 743 (2024).
Wu, Y. et al. Renalase Prevents Renal Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Down-Regulating GSK-3β/Snail Signaling. Int J. Med Sci. 20, 669–681 (2023).
Andrade-Silva, M. et al. The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis. Kidney Int 107, 302–316 (2025).
Chen, X., Shi, C., He, M., Xiong, S. & Xia, X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct. Target Ther. 8, 352 (2023).
Chen, L. W. et al. The Epstein-Barr Virus Lytic Protein BMLF1 Induces Upregulation of GRP78 Expression through ATF6 Activation. Int. J. Mol. Sci. 22, https://doi.org/10.3390/ijms22084024 (2021).
Yue, L. L. & Du, X. Thrombospondin 1 Promotes Endoplasmic Reticulum Stress and Apoptosis in HK-2 Cells by Upregulating ATF6-CHOP. Curr. Med Sci. 42, 341–347 (2022).
Sankrityayan, H., Kale, A., Shelke, V. & Gaikwad, A. B. Cyproheptadine, a SET7/9 inhibitor, reduces hyperglycaemia-induced ER stress alleviating inflammation and fibrosis in renal tubular epithelial cells. Arch. Physiol. Biochem 130, 411–419 (2024).
Chen, Y. Y. et al. Protein arginine methyltranferase-1 induces ER stress and epithelial-mesenchymal transition in renal tubular epithelial cells and contributes to diabetic nephropathy. Biochim Biophys. Acta Mol. Basis Dis. 1865, 2563–2575 (2019).
Zhu, L. R., Cui, W. & Liu, H. P. Molecular mechanisms of endoplasmic reticulum stress-mediated acute kidney injury in juvenile rats and the protective role of mesencephalic astrocyte-derived neurotrophic factor. J. Pharm. Pharm. 77, 609–620 (2025).
Guo, S. et al. Endoplasmic Reticulum Stress-Mediated Cell Death in Renal Fibrosis. Biomolecules 14, https://doi.org/10.3390/biom14080919 (2024).
Qian, X. et al. SMN haploinsufficiency promotes ischemia/ reperfusion-induced AKI-to-CKD transition by endoplasmic reticulum stress activation. Faseb J. 37, e23276 (2023).
Li, L. et al. Tauroursodeoxycholic acid inhibits TGF-β1-induced renal fibrosis markers in cultured renal mesangial cells by regulating endoplasmic reticulum stress. Exp. Ther. Med. 23, 432 (2022).
Zhao, H. et al. Poricoic acid A attenuates renal fibrosis by inhibiting endoplasmic reticulum stress-mediated apoptosis. Braz. J. Med Biol. Res. 57, e14249 (2024).
Smith, T. M., Wang, X., Zhang, W., Kulyk, W. & Nazarali, A. J. Hoxa2 plays a direct role in murine palate development. Dev. Dyn. 238, 2364–2373 (2009).
Bridoux, L., Deneyer, N., Bergiers, I. & Rezsohazy, R. Molecular Analysis of the HOXA2-Dependent Degradation of RCHY1. PLoS One 10, e0141347 (2015).
Liu, Z. et al. Abnormally high expression of HOXA2 as an independent factor for poor prognosis in glioma patients. Cell Cycle 19, 1632–1640 (2020).
Zong, X., Fu, J., Wang, Z. & Wang, Q. The Diagnostic and Prognostic Values of HOXA Gene Family in Kidney Clear Cell Renal Cell Carcinoma. J. Oncol. 2022, 1762637 (2022).
Jiang, M. et al. LncRNA-LINC00472 suppresses the malignant progression of non-small cell lung cancer via modulation of the miRNA-1275/Homeobox A2 axis. Adv. Clin. Exp. Med 33, 283–297 (2024).
Samarelli, A. V. et al. Expression of HOXB7 in the Lung of Patients with Idiopathic Pulmonary Fibrosis: A Proof-of-Concept Study. Biomedicines 12, https://doi.org/10.3390/biomedicines12061321 (2024).
Zhang, N., Guo, F. & Song, Y. HOXC8/TGF-β1 positive feedback loop promotes liver fibrosis and hepatic stellate cell activation via activating Smad2/Smad3 signaling. Biochem Biophys. Res Commun. 662, 39–46 (2023).
Peng, L. et al. HOXA13 exerts a beneficial effect in albumin-induced epithelial-mesenchymal transition via the glucocorticoid receptor signaling pathway in human renal tubular epithelial cells. Mol. Med Rep. 14, 271–276 (2016).
Li, X. et al. HOXD10 attenuates renal fibrosis by inhibiting NOX4-induced ferroptosis. Cell Death Dis. 15, 398 (2024).
Xiao, X. et al. Hypermethylation leads to the loss of HOXA5, resulting in JAG1 expression and NOTCH signaling contributing to kidney fibrosis. Kidney Int 106, 98–114 (2024).
Zeybel, M. et al. DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease. Clin. Epigenetics 8, 48 (2016).
Wu, H., Qiu, Z., Wang, L. & Li, W. Renal Fibrosis: SIRT1 Still of Value. Biomedicines 12, https://doi.org/10.3390/biomedicines12091942 (2024).
Hu, H. et al. SIRT1 regulates endoplasmic reticulum stress-related organ damage. Acta Histochem 126, 152134 (2024).
Kim, H. et al. Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin. Int. J. Mol. Sci. 18, https://doi.org/10.3390/ijms18020305 (2017).
Chang, J. W. et al. Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis. Nephron 133, 116–128 (2016).
Kim, H., Baek, C. H., Chang, J. W., Yang, W. S. & Lee, S. K. Febuxostat, a novel inhibitor of xanthine oxidase, reduces ER stress through upregulation of SIRT1-AMPK-HO-1/thioredoxin expression. Clin. Exp. Nephrol. 24, 205–215 (2020).
Zhou, W. et al. Dihydroartemisinin suppresses renal fibrosis in mice by inhibiting DNA-methyltransferase 1 and increasing Klotho. Acta Pharm. Sin. 43, 2609–2623 (2022).
Chen, Z. et al. lncRNA HOTAIRM1 promotes osteogenesis of hDFSCs by epigenetically regulating HOXA2 via DNMT1 in vitro. J. Cell Physiol. 235, 8507–8519 (2020).
Kim, H. et al. Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis. Am. J. Physiol. Ren. Physiol. 308, F226–236 (2015).
Guo, R. et al. SIRT1 suppresses cardiomyocyte apoptosis in diabetic cardiomyopathy: An insight into endoplasmic reticulum stress response mechanism. Int J. Cardiol. 191, 36–45 (2015).
Benedetti, R. et al. ATF6 supports lysosomal function in tumor cells to enable ER stress-activated macroautophagy and CMA: impact on mutant TP53 expression. Autophagy 20, 1854–1867 (2024).
Wu, D. et al. Unfolded protein response factor ATF6 augments T helper cell responses and promotes mixed granulocytic airway inflammation. Mucosal Immunol. 16, 499–512 (2023).
Zhou, R. et al. Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism. Cell Physiol. Biochem 51, 2397–2420 (2018).
Wu, Q. et al. Polystyrene nanoplastics-induced lung apoptosis and ferroptosis via ROS-dependent endoplasmic reticulum stress. Sci. Total Environ. 912, 169260 (2024).
Zhou, Y. et al. TGF-β1 induces ROS to activate ferroptosis via the ERK1/2-WISP1 pathway to promote the progression of renal tubular epithelial cell fibrosis. Cytotechnology 77, 61 (2025).
Makhammajanov, Z. et al. Tubular toxicity of proteinuria and the progression of chronic kidney disease. Nephrol. Dial. Transpl. 39, 589–599 (2024).
Tsai, L. T. et al. Inhibition of Indoxyl Sulfate-Induced Reactive Oxygen Species-Related Ferroptosis Alleviates Renal Cell Injury In Vitro and Chronic Kidney Disease Progression In Vivo. Antioxidants (Basel) 12, https://doi.org/10.3390/antiox12111931 (2023).
Cao, Y. et al. Danshen injection ameliorates unilateral ureteral obstruction-induced renal fibrosis by inhibiting ferroptosis via activating SIRT1/GPX4 pathway. Front Pharm. 15, 1503628 (2024).
Tian, J. et al. SIRT1 slows the progression of lupus nephritis by regulating the NLRP3 inflammasome through ROS/TRPM2/Ca(2+) channel. Clin. Exp. Med 23, 3465–3478 (2023).
Sun, H. J. et al. Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3. Redox Biol. 38, 101813 (2021).
Yuan, Q. et al. MiR-185-5p ameliorates endoplasmic reticulum stress and renal fibrosis by downregulation of ATF6. Lab Invest 100, 1436–1446 (2020).
Khan, I., Amin, M. A., Eklund, E. A. & Gartel, A. L. Regulation of HOX gene expression in AML. Blood Cancer J. 14, 42 (2024).
Song, Y. P. et al. Comprehensive Landscape of HOXA2, HOXA9, and HOXA10 as Potential Biomarkers for Predicting Progression and Prognosis in Prostate Cancer. J. Immunol. Res 2022, 5740971 (2022).
De Palma, F. D. E. et al. Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival. Cell Death Differ. 32, 730–744 (2025).
Mohan, K. N. DNMT1: catalytic and non-catalytic roles in different biological processes. Epigenomics 14, 629–643 (2022).
Chen, Q. Q. et al. Neuraminidase 1 promotes renal fibrosis development in male mice. Nat. Commun. 14, 1713 (2023).
Adachi, E. et al. Progranulin deficiency attenuates tubulointerstitial injury in a mouse unilateral ureteral obstruction model. Exp. Anim. 73, 293–301 (2024).
Rouschop, K. M. et al. CD44 deficiency increases tubular damage but reduces renal fibrosis in obstructive nephropathy. J. Am. Soc. Nephrol. 15, 674–686 (2004).
Badid, C. et al. Interstitial expression of alpha-SMA: an early marker of chronic renal allograft dysfunction. Nephrol. Dial. Transpl. 17, 1993–1998 (2002).
Li, X. et al. MYCT1 attenuates renal fibrosis and tubular injury in diabetic kidney disease. iScience 26, 107609 (2023).
Loos, B. et al. TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis. Cell Death Dis. 15, 925 (2024).
Li, X. et al. YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/HIF-1α pathway. Front Pharm. 14, 1069348 (2023).
Yang, J. W. et al. Didymin alleviates metabolic dysfunction-associated fatty liver disease (MAFLD) via the stimulation of Sirt1-mediated lipophagy and mitochondrial biogenesis. J. Transl. Med. 21, 921 (2023).
Neveu, W. A., Mills, S. T., Staitieh, B. S. & Sueblinvong, V. TGF-β1 epigenetically modifies Thy-1 expression in primary lung fibroblasts. Am. J. Physiol. Cell Physiol. 309, C616–626 (2015).
Li, P. et al. An improved cell nuclear isolation method. Biol. Methods Protoc. 10, bpaf007 (2025).
Acknowledgements
We thank for the support from Department of Nephrology, Neurology and Anesthesiology of Fourth Affiliated Hospital of China Medical University, Department of Biological Therapy of First Affiliated Hospital of China Medical University and Department of Pathology of Shengjing Hospital of China Medical University. The study was supported by the National Natural Science Foundation of China (82402721), Liaoning Province Postdoctoral Science Fund (3110211225) and Science and Technology Project of Liaoning Province (2025080736-JH3/101).
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All authors approved final version of manuscript. X.L., T.M., X.D., H.L., Y.L. and H.D. conceived and designed research and performed experiments. S.H., F.M., Y.Z., Q.Y. X.D. and X.L. analyzed data. X.L., T.M., H.L. and Y.L. prepared figures and edited text. X.L., T.M., and X.D. drafted manuscript. H.L., Y.L., and H.D. edited and revised manuscript. H.L., Y.L., and H.D. given final approval of the version to be published.
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Li, X., Ma, TK., Deng, XX. et al. HOXA2 exerts anti-renal fibrosis effects through reducing endoplasmic reticulum stress via the upregulation of SIRT1. Commun Biol (2025). https://doi.org/10.1038/s42003-025-09453-2
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DOI: https://doi.org/10.1038/s42003-025-09453-2
