Interplay of cGAS-STING and ferroptosis: crosstalk, molecular mechanisms, and therapeutic prospects

Yumin Wang^#¹, Shuang Wu^#², Yitong Wang^#³, Clara Xi Wang⁴, Weihua Zheng⁵, Xia Yun⁶, Zhiji Wang⁷, Junjing Zhang^#⁵, Lida Du⁸, Hongquan Wang^{9

10

11}

Affiliations

¹ Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China.
² Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China.
³ Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China.
⁴ School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19103, USA.
⁵ Department of Hepato-Biliary Surgery, Department of Surgery, Hohhot First Hospital, Hohhot, 010030, China.
⁶ Teaching Department, Hohhot First Hospital, Hohhot, 010030, China.
⁷ Division of Neurobiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
⁸ Division of Neurobiology, Johns Hopkins University, Baltimore, MD, 21205, USA. ldu13@jh.edu.
⁹ Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China. whongquan@alu.fudan.edu.cn.
¹⁰ Department of Neurology, Hohhot First Hospital, Hohhot, 010030, China. whongquan@alu.fudan.edu.cn.
¹¹ Aerospace Medical Center, Aerospace Center Hospital, Beijing, 100049, China. whongquan@alu.fudan.edu.cn.

^# Contributed equally.

PMID: 40828197
DOI: 10.1007/s00204-025-04150-9

Review

Interplay of cGAS-STING and ferroptosis: crosstalk, molecular mechanisms, and therapeutic prospects

Yumin Wang et al. Arch Toxicol. 2025.

. 2025 Aug 19.

doi: 10.1007/s00204-025-04150-9. Online ahead of print.

Authors

Yumin Wang^#¹, Shuang Wu^#², Yitong Wang^#³, Clara Xi Wang⁴, Weihua Zheng⁵, Xia Yun⁶, Zhiji Wang⁷, Junjing Zhang^#⁵, Lida Du⁸, Hongquan Wang^{9

10

11}

Affiliations

¹ Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China.
² Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China.
³ Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China.
⁴ School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19103, USA.
⁵ Department of Hepato-Biliary Surgery, Department of Surgery, Hohhot First Hospital, Hohhot, 010030, China.
⁶ Teaching Department, Hohhot First Hospital, Hohhot, 010030, China.
⁷ Division of Neurobiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
⁸ Division of Neurobiology, Johns Hopkins University, Baltimore, MD, 21205, USA. ldu13@jh.edu.
⁹ Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China. whongquan@alu.fudan.edu.cn.
¹⁰ Department of Neurology, Hohhot First Hospital, Hohhot, 010030, China. whongquan@alu.fudan.edu.cn.
¹¹ Aerospace Medical Center, Aerospace Center Hospital, Beijing, 100049, China. whongquan@alu.fudan.edu.cn.

^# Contributed equally.

PMID: 40828197
DOI: 10.1007/s00204-025-04150-9

Abstract

The cGAS-STING pathway, a crucial cytosolic DNA sensor, initiates innate immune responses by detecting microbial and aberrant self-DNA. This evolutionarily conserved axis plays pivotal roles in autoimmune disorders, sterile inflammation, and cellular senescence. While transient activation confers protective immunity, dysregulated cGAS-STING signaling drives pathogenesis in inflammatory and autoimmune diseases. Emerging evidence reveals its functional convergence with diverse cell death modalities-notably ferroptosis, an iron-dependent regulated cell death driven by lipid peroxidation. Their dynamic interplay emerges as a key pathogenic mechanism across diseases, offering novel therapeutic opportunities. This review first outlines the core molecular architecture of cGAS-STING signaling and its disease roles. We then analyze the mechanisms and pathophysiological consequences of cGAS-STING-ferroptosis crosstalk in various disorders, followed by advances in therapeutic strategies targeting this interface. Finally, we discuss translational challenges and propose innovative solutions. By highlighting the therapeutic potential of pharmacologically modulating this nexus, we identify a promising treatment for diseases with inflammatory conditions.

Keywords: Antagonist; Ferroptosis; Inhibitor; Interplay; cGAS-STING.

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Conflict of interest statement

Declarations. Conflict of interest: The authors have no competing financial or nonfinancial interests to disclose. Ethical approval and consent to participation: Not applicable. Consent for publication: Not applicable.

References

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Interplay of cGAS-STING and ferroptosis: crosstalk, molecular mechanisms, and therapeutic prospects

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Interplay of cGAS-STING and ferroptosis: crosstalk, molecular mechanisms, and therapeutic prospects

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