10-Gingerol attenuates alcohol-induced colon injury by modulating IL-36R and downstream cGAS-STING signaling to suppress macrophage inflammation and ferroptosis.
Abstract
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.