Journal of ethnopharmacology · 2026
10-Gingerol attenuates alcohol-induced colon injury by modulating IL-36R and downstream cGAS-STING signaling to suppress macrophage inflammation and ferroptosis.
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Li Miao, Wang Tian-Tian, Huang Yan-Ni, Wang Xin-Xin, Wang Hong-Zhang, Huo Xiao-Kui, Wang Yan, Lv Hui-Yi, Shang Yue
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Ginger (Zingiber officinale Roscoe, Zingiberaceae) is traditionally used in Chinese and Ayurvedic/Tibb-Unani medicine for gastrointestinal and inflammatory disorders. Its bioactive constituent 10-gingerol (10-G) exhibits intestinal anti-inflammatory activity, providing a rationale for investigating its protective effects against alcohol-induced colon injury.
AIM OF THE STUDY: To investigate whether 10-G attenuates alcohol-induced colon injury by modulating interleukin-36 receptor (IL-36R) and downstream cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, thereby reducing macrophage inflammation and ferroptosis.
MATERIALS AND METHODS: An alcohol-induced mouse colon injury model and lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages (MPMs) were used. Transcriptomics, Il1rl2 knockdown, complementary target-engagement assays, and STING-agonist rescue were performed.
RESULTS: 10-G reduced IL-36R and cGAS expression and STING signaling activation, while attenuating alcohol-induced colon injury, tight-junction disruption, inflammation, and ferroptosis-related alterations. Target-engagement assays supported IL-36R engagement by 10-G. In vivo, Il1rl2 knockdown suppressed cGAS-STING signaling and attenuated inflammation- and ferroptosis-related alterations. In LPS-stimulated MPMs, 10-G attenuated inflammatory responses and ferroptosis. Il1rl2 knockdown induced changes consistent with 10-G treatment; significant shRNA × 10-G interactions indicated that the effects of 10-G were influenced by IL-36R functional status. STING reactivation counteracted the effects of 10-G and Il1rl2 knockdown on inflammatory and ferroptosis-related readouts without restoring IL-36R levels.
CONCLUSIONS: 10-G attenuates alcohol-induced colon injury by engaging and modulating IL-36R and suppressing downstream cGAS-STING signaling, thereby reducing macrophage inflammation and ferroptosis. Genetic and pharmacological evidence supports a functional upstream role for IL-36R.
AIM OF THE STUDY: To investigate whether 10-G attenuates alcohol-induced colon injury by modulating interleukin-36 receptor (IL-36R) and downstream cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, thereby reducing macrophage inflammation and ferroptosis.
MATERIALS AND METHODS: An alcohol-induced mouse colon injury model and lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages (MPMs) were used. Transcriptomics, Il1rl2 knockdown, complementary target-engagement assays, and STING-agonist rescue were performed.
RESULTS: 10-G reduced IL-36R and cGAS expression and STING signaling activation, while attenuating alcohol-induced colon injury, tight-junction disruption, inflammation, and ferroptosis-related alterations. Target-engagement assays supported IL-36R engagement by 10-G. In vivo, Il1rl2 knockdown suppressed cGAS-STING signaling and attenuated inflammation- and ferroptosis-related alterations. In LPS-stimulated MPMs, 10-G attenuated inflammatory responses and ferroptosis. Il1rl2 knockdown induced changes consistent with 10-G treatment; significant shRNA × 10-G interactions indicated that the effects of 10-G were influenced by IL-36R functional status. STING reactivation counteracted the effects of 10-G and Il1rl2 knockdown on inflammatory and ferroptosis-related readouts without restoring IL-36R levels.
CONCLUSIONS: 10-G attenuates alcohol-induced colon injury by engaging and modulating IL-36R and suppressing downstream cGAS-STING signaling, thereby reducing macrophage inflammation and ferroptosis. Genetic and pharmacological evidence supports a functional upstream role for IL-36R.