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Updated: Jun 7, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
STING signaling contributes to methotrexate-induced liver injury by regulating ferroptosis in mice
Hong-Fei Wang1, Yu-Qiong He2, Zong Ke1
1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Abstract:
Methotrexate (MTX), an anti-metabolite agent, is a widely used chemotherapeutic anticancer drug, but its hepatotoxicity severely limits its clinical application. Nevertheless, the precise mechanisms of MTX-caused liver damage are extremely intricate and still need to be fully clarified. In the current study, we investigated the role of the STING-ERS-ferroptosis axis in MTX-triggered hepatic toxicity in vivo and in vitro models. Male C57BL/6 J mice exposed to a single dose of MTX (0, 2, 5, and 20 mg/kg) for 3 days exhibited severe liver damage and overactivated STING signaling. Moreover, we found that ferroptosis was also involved in MTX-mediated liver damage. Interestingly, STING deficiency alleviated liver damage, inhibited liver inflammation, as well as suppressed hepatic lipid peroxidation and ferroptosis in MTX-treated mice. Consistently, STING inhibitor (C-176) pretreatment also alleviated MTX-induced STING signaling activation, ROS overproduction and ferroptosis in AML12 cells. Finally, we verified that ER stress was responsible for the MTX-induced liver injury and ferroptosis caused by STING activation. Taken together, our study uncovered a novel link between STING signaling and ferroptosis in MTX-triggered hepatic damages, and suggested that targeting the STING-ER stress-ferroptosis axis might be a promising and effective therapeutic approach against MTX-induced liver damage.
Insights
Methotrexate (MTX) causes liver damage through STING signaling, endoplasmic reticulum (ER) stress, and ferroptosis. Targeting this STING-ER stress-ferroptosis axis may offer a new therapy for MTX-induced liver injury.
Area of Science:
- Hepatology
- Immunology
- Cellular Biology
Background:
- Methotrexate (MTX) is a vital chemotherapy drug, but its use is limited by severe liver toxicity.
- The exact mechanisms behind MTX-induced liver damage remain incompletely understood.
- Investigating novel molecular pathways is crucial for mitigating MTX hepatotoxicity.
Purpose of the Study:
- To elucidate the role of the STING-ERS-ferroptosis axis in MTX-induced liver injury.
- To explore potential therapeutic strategies targeting this pathway.
Main Methods:
- Utilized in vivo mouse models and in vitro cell culture (AML12 cells).
- Administered varying doses of MTX to mice and assessed liver damage and STING signaling.
- Employed STING deficiency and a STING inhibitor (C-176) to evaluate their effects on MTX toxicity.
- Analyzed endoplasmic reticulum (ER) stress, reactive oxygen species (ROS), and ferroptosis markers.
Main Results:
- MTX treatment led to significant liver damage and STING pathway overactivation in mice.
- Ferroptosis was identified as a key component of MTX-mediated liver damage.
- STING deficiency or inhibition reduced liver injury, inflammation, lipid peroxidation, and ferroptosis in MTX-exposed models.
- ER stress was confirmed to mediate MTX-induced liver injury and ferroptosis via STING activation.
Conclusions:
- A novel link between STING signaling, ER stress, and ferroptosis in MTX-induced hepatotoxicity was uncovered.
- The STING-ER stress-ferroptosis axis represents a promising therapeutic target for managing MTX liver damage.
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