Research progress on targeting the GCH1-BH4 ferroptosis key pathway for improving the prognosis of acute kidney injury_West China Medical Journal

Authors：

LI Kan ¹ , LI Yan ¹ , AN Haiqian ¹ , MAO Zhiguo ² , LIU Disheng ³ , CHEN Qiming ⁴ ,  LIU Tianxi ¹

1. Department of Nephrology, the First Hospital of Lanzhou University, Lanzhou, Gansu 730030, P. R. China;
2. Department of Nephrology, the Second Affiliated Hospital of Naval Medical University of Chinese People’s Liberation Army, Shanghai 200001, P. R. China;
3. Department of Urology, the First Hospital of Lanzhou University, Lanzhou, Gansu 730030, P. R. China;
4. Intensive Care Unit, the First Hospital of Lanzhou University, Lanzhou, Gansu 730030, P. R. China;

Corresponding?author：

LIU Tianxi, Email: liutianxi@medmail.com.cn

Keywords：

Acute kidney injury; ferroptosis; guanosine triphosphate cyclohydrolase 1; tetrahydrobiopterin; targeted therapy

DOI：

10.7507/1002-0179.202512370

Video：

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Abstract Full text Figures/Tables Video References Cited by

This review aims to systematically elaborate on the core mechanisms of ferroptosis in acute kidney injury (AKI), and to deeply dissect the molecular basis by which the guanosine triphosphate cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway inhibits ferroptosis through pathways such as regulating the coenzyme Q10 system and reconstructing the lipid metabolic network. On this basis, the article focuses on exploring therapeutic strategies targeting the GCH1-BH4 axis, including the latest research progress and application potential of GCH1 agonists, gene therapy, and nanomedicine delivery systems in experimental AKI models.

Citation： LI Kan, LI Yan, AN Haiqian, MAO Zhiguo, LIU Disheng, CHEN Qiming, LIU Tianxi. Research progress on targeting the GCH1-BH4 ferroptosis key pathway for improving the prognosis of acute kidney injury. West China Medical Journal, 2026, 41(7): 1176-1181. doi: 10.7507/1002-0179.202512370 Copy

1.	Basile DP, Anderson MD, Sutton TA. Pathophysiology of acute kidney injury[J]. Compr Physiol, 2012, 2(2): 1303-1353.
2.	Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072.
3.	Hu J, Gu W, Ma N, et al. Leonurine alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signalling pathway[J]. Br J Pharmacol, 2022, 179(15): 3991-4009.
4.	Qiao O, Wang X, Wang Y, et al. Ferroptosis in acute kidney injury following crush syndrome: a novel target for treatment[J]. J Adv Res, 2023, 54: 211-222.
5.	Zheng Q, Xing J, Li X, et al. PRDM16 suppresses ferroptosis to protect against sepsis-associated acute kidney injury by targeting the NRF2/GPX4 axis[J]. Redox Biol, 2024, 78: 103417.
6.	Fanet H, Capuron L, Castanon N, et al. Tetrahydrobioterin (BH4) pathway: from metabolism to neuropsychiatry[J]. Curr Neuropharmacol, 2021, 19(5): 591-609.
7.	Kraft VAN, Bezjian CT, Pfeiffer S, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling[J]. ACS Cent Sci, 2020, 6(1): 41-53.
8.	Long Z, Luo Y, Yu M, et al. Targeting ferroptosis: a new therapeutic opportunity for kidney diseases[J]. Front Immunol, 2024, 15: 1435139.
9.	Jiang Y, Zhang M, Sun M. ACSL4 at the helm of the lipid peroxidation ship: a deep-sea exploration towards ferroptosis[J]. Front Pharmacol, 2025, 16: 1594419.
10.	Bouchaoui H, Mahoney-Sanchez L, Gar?on G, et al. ACSL4 and the lipoxygenases 15/15B are pivotal for ferroptosis induced by iron and PUFA dyshomeostasis in dopaminergic neurons[J]. Free Radic Biol Med, 2023, 195: 145-157.
11.	Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis[J]. Nature, 2019, 575(7784): 688-692.
12.	Martín-Saiz L, Guerrero-Mauvecin J, Martín-Sanchez D, et al. Ferrostatin-1 modulates dysregulated kidney lipids in acute kidney injury[J]. J Pathol, 2022, 257(3): 285-299.
13.	Wang Y, Quan F, Cao Q, et al. Quercetin alleviates acute kidney injury by inhibiting ferroptosis[J]. J Adv Res, 2020, 28: 231-243.
14.	Shi Z, Du Y, Zheng J, et al. Liproxstatin-1 alleviated ischemia/reperfusion-induced acute kidney injury via inhibiting ferroptosis[J]. Antioxidants (Basel), 2024, 13(2): 182.
15.	Belavgeni A, Meyer C, Stumpf J, et al. Ferroptosis and necroptosis in the kidney[J]. Cell Chem Biol, 2020, 27(4): 448-462.
16.	Jin X, He R, Lin Y, et al. Shenshuaifu granule attenuates acute kidney injury by inhibiting ferroptosis mediated by p53/SLC7A11/GPX4 pathway[J]. Drug Des Devel Ther, 2023, 17: 3363-3383.
17.	Liang NN, Guo YY, Zhang XY, et al. Mitochondrial dysfunction-evoked DHODH acetylation is involved in renal cell ferroptosis during cisplatin-induced acute kidney injury[J]. Adv Sci (Weinh), 2024, 11(43): e2404753.
18.	Li B, Lin F, Song B, et al. The long non-coding RNA RSDR protects against acute kidney injury in mice by interacting with hnRNPK to regulate DHODH-mediated ferroptosis[J]. Nat Commun, 2025, 16(1): 7483.
19.	Soula M, Weber RA, Zilka O, et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers[J]. Nat Chem Biol, 2020, 16(12): 1351-1360.
20.	Lin H, Pan J, Zhang J, et al. Intermedin protects peritubular capillaries by inhibiting eNOS uncoupling through AMPK/GTPCH-I/BH4 pathway and alleviate CKD following AKI[J]. Free Radic Biol Med, 2025, 234: 72-85.
21.	Song YH, Lei HX, Yu D, et al. Endogenous chemicals guard health through inhibiting ferroptotic cell death[J]. Biofactors, 2024, 50(2): 266-293.
22.	Li P, Yin YL, Guo T, et al. Inhibition of aberrant microRNA-133a expression in endothelial cells by statin prevents endothelial dysfunction by targeting GTP cyclohydrolase 1 in vivo[J]. Circulation, 2016, 134(22): 1752-1765.
23.	Xia N, Daiber A, Habermeier A, et al. Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice[J]. J Pharmacol Exp Ther, 2010, 335(1): 149-154.
24.	Rahmania L, Orbegozo D, Su F, et al. Administration of tetrahydrobiopterin (BH4) protects the renal microcirculation from ischemia and reperfusion injury[J]. Anesth Analg, 2017, 125(4): 1253-1260.
25.	Ni L, Yuan C, Wu X. Targeting ferroptosis in acute kidney injury[J]. Cell Death Dis, 2022, 13(2): 182.
26.	Lyu G, Liao H, Li R. Ferroptosis and renal fibrosis: mechanistic insights and emerging therapeutic targets[J]. Ren Fail, 2025, 47(1): 2498629.
27.	Li Y, Li K, Zhao W, et al. VPA improves ferroptosis in tubular epithelial cells after cisplatin-induced acute kidney injury[J]. Front Pharmacol, 2023, 14: 1147772.
28.	Gama P, Cadena-Nava RD, Juarez-Moreno K, et al. Virus-based nanoreactors with GALT activity for classic galactosemia therapy[J]. ChemMedChem, 2021, 16(9): 1438-1445.
29.	Peng C, Huang Y, Zheng J. Renal clearable nanocarriers: overcoming the physiological barriers for precise drug delivery and clearance[J]. J Control Release, 2020, 322: 64-80.
30.	Sun C, Yang H, Yuan Y, et al. Controlling assembly of paired gold clusters within apoferritin nanoreactor for in vivo kidney targeting and biomedical imaging[J]. J Am Chem Soc, 2011, 133(22): 8617-8624.
31.	Yang X, Wang L, Li L, et al. A novel dendrimer-based complex co-modified with cyclic RGD hexapeptide and penetratin for noninvasive targeting and penetration of the ocular posterior segment[J]. Drug Deliv, 2019, 26(1): 989-1001.
32.	Xie J, Ye Z, Li L, et al. Ferrostatin-1 alleviates oxalate-induced renal tubular epithelial cell injury, fibrosis and calcium oxalate stone formation by inhibiting ferroptosis[J]. Mol Med Rep, 2022, 26(2): 256.
33.	Asensio Lopez MDC, Lax A, Hernandez Vicente A, et al. Empagliflozin improves post-infarction cardiac remodeling through GTP enzyme cyclohydrolase 1 and irrespective of diabetes status[J]. Sci Rep, 2020, 10(1): 13553.
34.	Zhao Y, Gong M, Liu X, et al. Noninvasive DWI tracking of hiPSCs differentiation into RTECs in AKI recovery via the KSP promoter-mediated AQP1 strategy[J]. Theranostics, 2025, 15(11): 5106-5120.
35.	Han S, Lin F, Ruan Y, et al. miR-132-3p promotes the cisplatin-induced apoptosis and inflammatory response of renal tubular epithelial cells by targeting SIRT1 via the NF-κB pathway[J]. Int Immunopharmacol, 2021, 99: 108022.
36.	Hernandez-Navarro I, Botana L, Diez-Mata J, et al. Replicative endothelial cell senescence may lead to endothelial dysfunction by increasing the BH2/BH4 ratio induced by oxidative stress, reducing BH4 availability, and decreasing the expression of eNOS[J]. Int J Mol Sci, 2024, 25(18): 9890.
37.	Starr A, Sand CA, Heikal L, et al. Overexpression of GTP cyclohydrolase 1 feedback regulatory protein is protective in a murine model of septic shock[J]. Shock, 2014, 42(5): 432-439.

1. Basile DP, Anderson MD, Sutton TA. Pathophysiology of acute kidney injury[J]. Compr Physiol, 2012, 2(2): 1303-1353.
2. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072.
3. Hu J, Gu W, Ma N, et al. Leonurine alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signalling pathway[J]. Br J Pharmacol, 2022, 179(15): 3991-4009.
4. Qiao O, Wang X, Wang Y, et al. Ferroptosis in acute kidney injury following crush syndrome: a novel target for treatment[J]. J Adv Res, 2023, 54: 211-222.
5. Zheng Q, Xing J, Li X, et al. PRDM16 suppresses ferroptosis to protect against sepsis-associated acute kidney injury by targeting the NRF2/GPX4 axis[J]. Redox Biol, 2024, 78: 103417.
6. Fanet H, Capuron L, Castanon N, et al. Tetrahydrobioterin (BH4) pathway: from metabolism to neuropsychiatry[J]. Curr Neuropharmacol, 2021, 19(5): 591-609.
7. Kraft VAN, Bezjian CT, Pfeiffer S, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling[J]. ACS Cent Sci, 2020, 6(1): 41-53.
8. Long Z, Luo Y, Yu M, et al. Targeting ferroptosis: a new therapeutic opportunity for kidney diseases[J]. Front Immunol, 2024, 15: 1435139.
9. Jiang Y, Zhang M, Sun M. ACSL4 at the helm of the lipid peroxidation ship: a deep-sea exploration towards ferroptosis[J]. Front Pharmacol, 2025, 16: 1594419.
10. Bouchaoui H, Mahoney-Sanchez L, Gar?on G, et al. ACSL4 and the lipoxygenases 15/15B are pivotal for ferroptosis induced by iron and PUFA dyshomeostasis in dopaminergic neurons[J]. Free Radic Biol Med, 2023, 195: 145-157.
11. Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis[J]. Nature, 2019, 575(7784): 688-692.
12. Martín-Saiz L, Guerrero-Mauvecin J, Martín-Sanchez D, et al. Ferrostatin-1 modulates dysregulated kidney lipids in acute kidney injury[J]. J Pathol, 2022, 257(3): 285-299.
13. Wang Y, Quan F, Cao Q, et al. Quercetin alleviates acute kidney injury by inhibiting ferroptosis[J]. J Adv Res, 2020, 28: 231-243.
14. Shi Z, Du Y, Zheng J, et al. Liproxstatin-1 alleviated ischemia/reperfusion-induced acute kidney injury via inhibiting ferroptosis[J]. Antioxidants (Basel), 2024, 13(2): 182.
15. Belavgeni A, Meyer C, Stumpf J, et al. Ferroptosis and necroptosis in the kidney[J]. Cell Chem Biol, 2020, 27(4): 448-462.
16. Jin X, He R, Lin Y, et al. Shenshuaifu granule attenuates acute kidney injury by inhibiting ferroptosis mediated by p53/SLC7A11/GPX4 pathway[J]. Drug Des Devel Ther, 2023, 17: 3363-3383.
17. Liang NN, Guo YY, Zhang XY, et al. Mitochondrial dysfunction-evoked DHODH acetylation is involved in renal cell ferroptosis during cisplatin-induced acute kidney injury[J]. Adv Sci (Weinh), 2024, 11(43): e2404753.
18. Li B, Lin F, Song B, et al. The long non-coding RNA RSDR protects against acute kidney injury in mice by interacting with hnRNPK to regulate DHODH-mediated ferroptosis[J]. Nat Commun, 2025, 16(1): 7483.
19. Soula M, Weber RA, Zilka O, et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers[J]. Nat Chem Biol, 2020, 16(12): 1351-1360.
20. Lin H, Pan J, Zhang J, et al. Intermedin protects peritubular capillaries by inhibiting eNOS uncoupling through AMPK/GTPCH-I/BH4 pathway and alleviate CKD following AKI[J]. Free Radic Biol Med, 2025, 234: 72-85.
21. Song YH, Lei HX, Yu D, et al. Endogenous chemicals guard health through inhibiting ferroptotic cell death[J]. Biofactors, 2024, 50(2): 266-293.
22. Li P, Yin YL, Guo T, et al. Inhibition of aberrant microRNA-133a expression in endothelial cells by statin prevents endothelial dysfunction by targeting GTP cyclohydrolase 1 in vivo[J]. Circulation, 2016, 134(22): 1752-1765.
23. Xia N, Daiber A, Habermeier A, et al. Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice[J]. J Pharmacol Exp Ther, 2010, 335(1): 149-154.
24. Rahmania L, Orbegozo D, Su F, et al. Administration of tetrahydrobiopterin (BH4) protects the renal microcirculation from ischemia and reperfusion injury[J]. Anesth Analg, 2017, 125(4): 1253-1260.
25. Ni L, Yuan C, Wu X. Targeting ferroptosis in acute kidney injury[J]. Cell Death Dis, 2022, 13(2): 182.
26. Lyu G, Liao H, Li R. Ferroptosis and renal fibrosis: mechanistic insights and emerging therapeutic targets[J]. Ren Fail, 2025, 47(1): 2498629.
27. Li Y, Li K, Zhao W, et al. VPA improves ferroptosis in tubular epithelial cells after cisplatin-induced acute kidney injury[J]. Front Pharmacol, 2023, 14: 1147772.
28. Gama P, Cadena-Nava RD, Juarez-Moreno K, et al. Virus-based nanoreactors with GALT activity for classic galactosemia therapy[J]. ChemMedChem, 2021, 16(9): 1438-1445.
29. Peng C, Huang Y, Zheng J. Renal clearable nanocarriers: overcoming the physiological barriers for precise drug delivery and clearance[J]. J Control Release, 2020, 322: 64-80.
30. Sun C, Yang H, Yuan Y, et al. Controlling assembly of paired gold clusters within apoferritin nanoreactor for in vivo kidney targeting and biomedical imaging[J]. J Am Chem Soc, 2011, 133(22): 8617-8624.
31. Yang X, Wang L, Li L, et al. A novel dendrimer-based complex co-modified with cyclic RGD hexapeptide and penetratin for noninvasive targeting and penetration of the ocular posterior segment[J]. Drug Deliv, 2019, 26(1): 989-1001.
32. Xie J, Ye Z, Li L, et al. Ferrostatin-1 alleviates oxalate-induced renal tubular epithelial cell injury, fibrosis and calcium oxalate stone formation by inhibiting ferroptosis[J]. Mol Med Rep, 2022, 26(2): 256.
33. Asensio Lopez MDC, Lax A, Hernandez Vicente A, et al. Empagliflozin improves post-infarction cardiac remodeling through GTP enzyme cyclohydrolase 1 and irrespective of diabetes status[J]. Sci Rep, 2020, 10(1): 13553.
34. Zhao Y, Gong M, Liu X, et al. Noninvasive DWI tracking of hiPSCs differentiation into RTECs in AKI recovery via the KSP promoter-mediated AQP1 strategy[J]. Theranostics, 2025, 15(11): 5106-5120.
35. Han S, Lin F, Ruan Y, et al. miR-132-3p promotes the cisplatin-induced apoptosis and inflammatory response of renal tubular epithelial cells by targeting SIRT1 via the NF-κB pathway[J]. Int Immunopharmacol, 2021, 99: 108022.
36. Hernandez-Navarro I, Botana L, Diez-Mata J, et al. Replicative endothelial cell senescence may lead to endothelial dysfunction by increasing the BH2/BH4 ratio induced by oxidative stress, reducing BH4 availability, and decreasing the expression of eNOS[J]. Int J Mol Sci, 2024, 25(18): 9890.
37. Starr A, Sand CA, Heikal L, et al. Overexpression of GTP cyclohydrolase 1 feedback regulatory protein is protective in a murine model of septic shock[J]. Shock, 2014, 42(5): 432-439.

West China Medical Journal

Research progress on targeting the GCH1-BH4 ferroptosis key pathway for improving the prognosis of acute kidney injury

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