Mechanisms of Ferroptosis in Pancreatic β-Cell Dysfunction in Diabetes and Exploration of Therapeutic Targets

Diabetes mellitus is a highly prevalent chronic metabolic disease worldwide, with progressive pancreatic β-cell dysfunction recognized as the core pathological driver of disease onset and deterioration. Accumulating evidence over the past decade has identified ferroptosis, a novel iron-dependent form of regulated cell death, as a critical mediator of pancreatic β-cell injury in both type 1 and type 2 diabetes. Ferroptosis is triggered by intracellular iron overload, excessive lipid peroxidation, and impaired antioxidant defense systems, and its dysregulation has emerged as a key research focus in the field of diabetes pathogenesis. In this review, we systematically outline the core biological characteristics and canonical regulatory networks of ferroptosis, and elaborate the pathophysiological basis of pancreatic β-cell dysfunction in diabetes. We comprehensively dissect the multifaceted mechanisms by which ferroptosis drives β-cell impairment, including iron metabolism disorder, lipid peroxidation accumulation, glutathione-GPX4 antioxidant system imbalance, and the crosstalk between ferroptosis and other cellular stress pathways. Furthermore, we integrate the latest preclinical and clinical research advances from 2025 to 2026, summarize potential therapeutic targets and intervention strategies targeting ferroptosis to preserve β-cell function, and provide a critical evaluation of the feasibility, challenges, and clinical translation potential of these strategies. Finally, we highlight the unresolved key scientific questions in current research, propose concrete and actionable future research directions, and aim to provide a theoretical framework for the development of novel diabetes treatments targeting ferroptosis-mediated β-cell injury.

[1]       Harreiter, J., and Roden, M. 2023. “Diabetes Mellitus: Definition, Classification, Diagnosis, Screening and Prevention (Update 2023).” Wiener klinische Wochenschrift 135 (Suppl 1): 7-17.

[2]       Majety, P., Lozada Orquera, F. A., Edem, D., and Hamdy, O. 2023. “Pharmacological Approaches to the Prevention of Type 2 Diabetes Mellitus.” Frontiers in Endocrinology 14: 1118848.

[3]       Prasad, M. K., Mohandas, S., and Ramkumar, K. M. 2023. “Dysfunctions, Molecular Mechanisms, And Therapeutic Strategies of Pancreatic β-cells in Diabetes.” Apoptosis: An International Journal on Programmed Cell Death 28 (7-8): 958-976.

[4]       Novoselova, E. G., Lunin, S. M., Khrenov, M. O., Glushkova, O. V., Novoselova, T. V., and Parfenyuk, S. B. 2023. “The Possible Role of β-Cell Senescence in the Development of Type 2 Diabetes Mellitus. Cellular Physiology and Biochemistry.” International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology 57 (1): 34-48.

[5]       Prasad, M. K., Mohandas, S., and Ramkumar, K. M. (2023). “Dysfunctions, Molecular Mechanisms, and Therapeutic Strategies of Pancreatic β-cells in Diabetes.” Apoptosis: An International Journal on Programmed Cell Death 28 (7-8): 958-976.

[6]       Stockwell, B. R. 2022. “Ferroptosis Turns 10: Emerging Mechanisms, Physiological Functions, and Therapeutic Applications.” Cell 185 (14): 2401-2421.

[7]       Stancic, A., Saksida, T., Markelic, M., Vucetic, M., Grigorov, I., Martinovic, V., Gajic, D., Ivanovic, A., Velickovic, K., Savic, N., and Otasevic, V. 2022. “Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions.” Oxidative Medicine and Cellular Longevity: 3873420.

[8]       Díaz-López, A., Iglesias-Vázquez, L., Pallejà-Millán, M., Rey Reñones, C., Flores Mateo, G., and Arija, V. 2020. “Association Between Iron Status and Incident Type 2 Diabetes: A Population-Based Cohort Study.” Nutrients 12 (11): 3249.

[9]       Ding, Y., and Wu, Q. 2023. “1,25D/VDR Inhibits Pancreatic β-cell Ferroptosis by Downregulating FOXO1 Expression in Diabetes Mellitus.” Cellular Signaling 105: 110564.

[10]    Stockwell, B. R. 2022. “Ferroptosis Turns 10: Emerging Mechanisms, Physiological Functions, and Therapeutic Applications.” Cell 185 (14): 2401-2421.

[11]    Saad, H. M., Salem, E. A., Elhussieny, O., Waheeb, T. S., and Elsayed, A. E. 2025. “Crosstalk Between Ferroptosis and miRNA in Type 2 Diabetes Mellitus and Possible Therapeutic Targeting.” European Journal of Medical Research 30 (1): 982.

[12]    Miao, R., Fang, X., Zhang, Y., Wei, J., Zhang, Y., & Tian, J. (2023). Iron metabolism and ferroptosis in type 2 diabetes mellitus and complications: mechanisms and therapeutic opportunities. Cell death & disease, 14(3), 186.

[13]    Li, D., Jiang, C., Mei, G., Zhao, Y., Chen, L., Liu, J., Tang, Y., Gao, C., and Yao, P. 2020. “Quercetin Alleviates Ferroptosis of Pancreatic β Cells in Type 2 Diabetes.” Nutrients 12 (10): 2954.

[14]    Sha, W., Hu, F., Xi, Y., Chu, Y., and Bu, S. 2021. “Mechanism of Ferroptosis and Its Role in Type 2 Diabetes Mellitus.” Journal Of Diabetes Research 2021: 9999612.

[15]    Krümmel, B., von Hanstein, A. S., Plötz, T., Lenzen, S., and Mehmeti, I. 2022. “Differential Effects of Saturated and Unsaturated Free Fatty Acids on Ferroptosis in Rat β-cells.” The Journal of Nutritional Biochemistry 106: 109013.

[16]    Zhao, H., Li, R., Guo, X., Kang, J., Li, H., Wang, X., Wang, Y., Cui, H., Lv, S., Wen, W., and Zhang, Z. 2025. “Mechanism of Plantamajoside in Inhibiting Ferroptosis of Pancreatic β cells and Treatment of T2DM via Activation of the xCT/GPX4 Pathway.” PloS One 20 (6): e0325674.

[17]    Yue, S., Yaping, B., and De Guo W., et al. (2023). “Protective Effects of Metformin on Pancreatic β-cell Ferroptosis in Type 2 Diabetes in vivo.” Biomedecine & Pharmacotherapie 168: 115835-115835.

[18]    Zhao, H., Li, R., Guo, X., Kang, J., Li, H., Wang, X., Wang, Y., Cui, H., Lv, S., Wen, W., and Zhang, Z. 2025. “Mechanism of Plantamajoside in Inhibiting Ferroptosis of Pancreatic β cells and Treatment of T2DM via Activation of the xCT/GPX4 Pathway.” PloS One 20 (6): e0325674.

[19]    Stancic, A., Saksida, T., Markelic, M., Vucetic, M., Grigorov, I., Martinovic, V., Gajic, D., Ivanovic, A., Velickovic, K., Savic, N., and Otasevic, V. 2022. “Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions.” Oxidative Medicine and Cellular Longevity 2022: 3873420.

[20]    Yoo, S., Kim, D., Kim, M., Bae, J. Y., Lee, S. A., Kim, E. T., and Koh, G. 2025. “OTUB1 Modulates Ferroptosis by Regulating SLC7A11 Ubiquitination in Pancreatic β-Cells.” FASEB Journal 39 (20): e71128.

[21]    Díaz-López, A., Iglesias-Vázquez, L., Pallejà-Millán, M., Rey Reñones, C., Flores Mateo, G., and Arija, V. 2020. “Association between Iron Status and Incident Type 2 Diabetes: A Population-Based Cohort Study.” Nutrients 12 (11): 3249.

[22]    Sun, Y., Bai, Y. P., Wang, D. G., Xing, Y. J., Zhang, T., Wang, W., Zhou, S. M., Cheng, J. H., Chang, W. W., Kong, X., Yao, X. M., and Guo, L. Q. 2023. Protective Effects of Metformin on Pancreatic β-cell Ferroptosis in Type 2 Diabetes in Vivo.” Biomedecine & Pharmacotherapie 168: 115835.

[23]    Wang, N., Wang, J., Wu, Y., Qu, M., Hong, J., Cui, Z., Chen, Y., & Zhang, R. (2025). “Cynarin Counteracts Lipotoxicity in Pancreatic β-Cells Via Inhibiting Palmitate-Induced Apoptosis and Linoleic Acid-Provoked Ferroptosis.” Plant Foods for Human Nutrition (Dordrecht, Netherlands) 80 (3): 139.

[24]    Miao, R., Fang, X., Zhang, Y., Wei, J., Zhang, Y., and Tian, J. 2023. “Iron Metabolism and Ferroptosis in Type 2 Diabetes Mellitus and Complications: Mechanisms and Therapeutic Opportunities.” Cell Death & Disease 14 (3): 186.

[25]    Yoo, S., Kim, D., Kim, M., Bae, J. Y., Lee, S. A., Kim, E. T., and Koh, G. 2025. “OTUB1 Modulates Ferroptosis by Regulating SLC7A11 Ubiquitination in Pancreatic β-Cells.” FASEB Journal 39 (20): e71128.

[26]    Ding, Y., and Wu, Q. 2023. “1,25D/VDR Inhibits Pancreatic β Cell Ferroptosis by Downregulating FOXO1 Expression in Diabetes Mellitus.” Cellular Signaling 105: 110564.

[27]    Li, H., Zhang, H., Wang, T., Zhang, L., Wang, H., Lu, H., Yang, R., and Ding, Y. 2024. “Grape Seed Proanthocyanidins Protect Pancreatic β Cells Against Ferroptosis via the Nrf2 Pathway in Type 2 Diabetes.” Biological Trace Element Research 202 (12): 5531-5544.

[28]    Stancic, A., Saksida, T., Markelic, M., Vucetic, M., Grigorov, I., Martinovic, V., Gajic, D., Ivanovic, A., Velickovic, K., Savic, N., and Otasevic, V. 2022. “Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions.” Oxidative Medicine and Cellular Longevity 2022: 3873420.

[29]    Guan G., Liu J., and Zhang Q. et al. 2025. “NFAT5 Exacerbates β-cell Ferroptosis by Suppressing the Transcription of PRDX2 in Obese Type 2 Diabetes Mellitus.” Cellular and Molecular Life Sciences 82 (1): 64-64.

[30]    Fan, B., Yin, L., and Wang, A. et al. 2025. “PIM1 Enhances Insulin Secretion and Inhibits Ferroptosis of High Glucose-Induced Pancreatic β-cells Through Strengthening PINK1/Parkin-mediated Mitophagy via Inactivating JNK/p38 Signaling Pathway.” Tissue and Cell 93: 102722-102722.

[31]    Krümmel, B., von Hanstein, A. S., Plötz, T., Lenzen, S., and Mehmeti, I. 2022. “Differential Effects of Saturated and Unsaturated Free Fatty Acids on Ferroptosis in Rat β-cells.” The Journal of Nutritional Biochemistry 106: 109013.

[32]    Li, H., Zhang, H., Wang, T., Zhang, L., Wang, H., Lu, H., Yang, R., and Ding, Y. 2024. “Grape Seed Proanthocyanidins Protect Pancreatic β Cells Against Ferroptosis via the Nrf2 Pathway in Type 2 Diabetes.” Biological Trace Element Research 202 (12): 5531-5544.

[33]    Prasad, M. K., Jayasuriya, R., and Ramkumar K. M. 2026. Polydatin Attenuates Ferroptosis in Pancreatic β- Cells via Activation of the GPx4-Nrf2 Axis under Hyperglycemic Conditions. The Journal of nutrition, 156(2), 101284.

[34]    Stancic, A., Saksida, T., Markelic, M., Vucetic, M., Grigorov, I., Martinovic, V., Gajic, D., Ivanovic, A., Velickovic, K., Savic, N., and Otasevic, V. 2022. “Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions.” Oxidative Medicine and Cellular Longevity 2022: 3873420.

[35]    Novoselova, E. G., Lunin, S. M., Khrenov, M. O., Glushkova, O. V., Novoselova, T. V., & Parfenyuk, S. B. 2023. “The Possible Role of Β-Cell Senescence in the Development of Type 2 Diabetes Mellitus.” Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology 57 (1): 34-48.

[36]    Sun, Y., Bai, Y. P., Wang, D. G., Xing, Y. J., Zhang, T., Wang, W., Zhou, S. M., Cheng, J. H., Chang, W. W., Kong, X., Yao, X. M., and Guo, L. Q. 2023. “Protective Effects of Metformin on Pancreatic β-cell Ferroptosis in Type 2 Diabetes in Vivo.” Biomedecine & Pharmacotherapie 168: 115835.

[37]    Prasad, M. K., Jayasuriya, R., and Ramkumar, K. M. 2026. “Polydatin Attenuates Ferroptosis in Pancreatic β-Cells via Activation of the GPx4-Nrf2 Axis under Hyperglycemic Conditions.” The Journal of Nutrition 156 (2): 101284.

[38]    Novoselova, E. G., Lunin, S. M., Khrenov, M. O., Glushkova, O. V., Novoselova, T. V., and Parfenyuk, S. B. 2023. “The Possible Role of Β-Cell Senescence in the Development of Type 2 Diabetes Mellitus.” Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology 57 (1): 34-48.

[39]    Zhang, Y., Han, S., Liu, C., Zheng, Y., Li, H., Gao, F., Bian, Y., Liu, X., Liu, H., Hu, S., Li, Y., Chen, Z. J., Zhao, S., and Zhao, H. 2023. “THADA Inhibition in Mice Protects Against Type 2 Diabetes Mellitus by Improving Pancreatic β-cell Function and Preserving β-cell Mass.” Nature Communications 14 (1): 1020.

[40]    Liu, J., Zhang, Y., Shi, D., He, C., and Xia, G. 2023. “Vitamin D Alleviates Type 2 Diabetes Mellitus by Mitigating Oxidative Stress-Induced Pancreatic β-Cell Impairment.” Experimental and Clinical Endocrinology & Diabetes 131 (12): 656-666.

[41]    Chen, J., Fei, S., and Chan L. W. C. et al. 2025. “Inflammatory Signaling Pathways in Pancreatic β-cell: New Insights Into Type 2 Diabetes Pathogenesis.” Pharmacological Research 216: 107776.

[42]    Zhang, Y., Wang, C., and Zhang, P., et al. 2026. “Mitochondria-associated Programmed Cell Death in Pancreatic β cell of T2DM.” Apoptosis: An International Journal on Programmed Cell Death 31 (3): 84.

[43]    Liu, J., Zhang, Y., Shi, D., He, C., and Xia, G. 2023. “Vitamin D Alleviates Type 2 Diabetes Mellitus by Mitigating Oxidative Stress-Induced Pancreatic β-Cell Impairment.” Experimental And Clinical Endocrinology & Diabetes 131 (12): 656-666.

[44]    Saad, H. M., Salem, E. A., Elhussieny, O., Waheeb, T. S., and Elsayed, A. E. 2025. “Crosstalk Between Ferroptosis and miRNA in Type 2 Diabetes Mellitus and Possible Therapeutic Targeting.” European Journal of Medical Research 30 (1): 982.

[45]    Li, D., Jiang, C., Mei, G., Zhao, Y., Chen, L., Liu, J., Tang, Y., Gao, C., and Yao, P. 2020. “Quercetin Alleviates Ferroptosis of Pancreatic β Cells in Type 2 Diabetes.” Nutrients 12 (10): 2954.

[46]    Wang, N., Wang, J., Wu, Y., Qu, M., Hong, J., Cui, Z., Chen, Y., and Zhang R. 2025. “Cynarin Counteracts Lipotoxicity in Pancreatic β-Cells Via Inhibiting Palmitate-Induced Apoptosis and Linoleic Acid-Provoked Ferroptosis.” Plant Foods for Human Nutrition (Dordrecht, Netherlands) 80 (3): 139.

[47]    Sha, W., Hu, F., Xi, Y., Chu, Y., and Bu, S. 2021. “Mechanism of Ferroptosis and Its Role in Type 2 Diabetes Mellitus.” Journal of Diabetes Research 2021: 9999612.

[48]    Zhang, Y., Han, S., Liu, C., Zheng, Y., Li, H., Gao, F., Bian, Y., Liu, X., Liu, H., Hu, S., Li, Y., Chen, Z. J., Zhao, S., and Zhao, H. 2023. “THADA Inhibition in Mice Protects Against Type 2 Diabetes Mellitus by Improving Pancreatic β-cell Function and Preserving β-cell Mass.” Nature Communications 14 (1): 1020.

[49]    Chen J., Fei S., and Chan L. W. C. et al. 2025. “Inflammatory Signaling Pathways in Pancreatic β-cell: New Insights into Type 2 Diabetes Pathogenesis.” Pharmacological Research 216: 107776.

[50]    Yang, H., Chen, Y., Wu, G., Ren, P., Chen, T., Liu, J., Zhang, B., Ma, X., Jiang, F., Li, Y., Tao, L., and Shen, X. 2025. “Investigating the Role of 1,8-Cineole in Mitigating Ferroptosis in a HFSD/STZ Diabetes Mellitus Type 2-Induced Model: A GEO Data Analysis Approach.” European Journal of Pharmacology 1002: 177846.

[51]    Zhang, S., Liu, X., Wang, J., Yuan, F., and Liu, Y. 2022. “Targeting Ferroptosis with miR-144-3p to Attenuate Pancreatic β Cells Dysfunction via Regulating USP22/SIRT1 in Type 2 Diabetes. Diabetology & Metabolic Syndrome 14 (1): 89.

[52]    Wu, F., Shang, C., Jin, T., and Shi, L. 2023. “Hispidin Inhibits Ferroptosis Induced by High Glucose via the miR-15b-5p/GLS2 Axis in Pancreatic Beta Cells.” Evidence-based Complementary and Alternative Medicine 2023: 9428241.

[53]    Zhang, Q. W., Wang, Y., Tong, Z. Y., Li, C. P., and He, L. P. 2024. “Vitamin D May Play a Vital Role in Alleviating Type 2 Diabetes Mellitus by Modulating the Ferroptosis Signaling Pathway.” Hormone and Metabolic Research 56 (3): 193-196.