Key Takeaways & Executive Findings
- •• • Sch B (10, 20, 50 mg/kg) significantly reduced DAI and CMDI scores (P<0.05, 0.01) and increased colon length (P<0.05, 0.01) in TNBS-induced UC rats, demonstrating dose-dependent mucosal protection and clinical potential for reducing disease severity. • • Sch B upregulated Beclin-1 and elevated LC3-II/I ratio (P<0.01) while downregulating ATG16L1 and p62 (P<0.05, 0.01), indicating restoration of autophagic flux from initiation to degradation, a critical mechanism for clearing damaged organelles and mitigating epithelial injury. • • Sch B downregulated NLRP3, Caspase-1, and GSDMD protein expression (P<0.05, 0.01), directly inhibiting the pyroptosis pathway and reducing serum IL-6, TNF-α, and IL-1β levels (P<0.05, 0.01), thereby breaking the pyroptosis-inflammation cycle. • • The study establishes a causal link between autophagic flux normalization and pyroptosis suppression, with Sch B's multi-target effects offering a therapeutic advantage over single-target anti-inflammatory agents, though cell-level validation and autophagy blockade rescue experiments are needed to confirm causality.
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Abstract
Ulcerative colitis (UC) remains a clinical challenge due to inadequate mucosal healing and high relapse rates. This study investigates the therapeutic efficacy of schisandrin B (Sch B) in a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced rat model of UC, focusing on the interplay between autophagy and pyroptosis. SD rats were randomized into control, model, mesalazine (100 mg/kg), and Sch B low-, medium-, and high-dose (10, 20, 50 mg/kg) groups (n=10 per group). After 14 days of treatment, disease activity index (DAI), colon length, and colon mucosa damage index (CMDI) were assessed. Histopathology, serum cytokine levels (TNF-α, IL-6, IL-1β), and protein expression of autophagy markers (Beclin-1, LC3B, ATG16L1, p62) and pyroptosis pathway components (NLRP3, Caspase-1, GSDMD) were evaluated. Sch B significantly ameliorated weight loss, hematochezia, and colon shortening (P<0.05, 0.01), reduced DAI and CMDI scores, and attenuated mucosal edema, ulceration, and inflammatory infiltration. Serum IL-6, TNF-α, and IL-1β levels were markedly decreased (P<0.05, 0.01). Sch B upregulated Beclin-1 and increased LC3-II/I ratio (P<0.01), while downregulating ATG16L1, p62, NLRP3, Caspase-1, and GSDMD (P<0.05, 0.01). These findings indicate that Sch B restores autophagic flux homeostasis, thereby suppressing NLRP3/Caspase-1/GSDMD-mediated pyroptosis and reducing pro-inflammatory cytokine release. The normalization of autophagic flux is a critical upstream mechanism for Sch B's inhibition of colonic epithelial pyroptosis, offering a multi-target therapeutic strategy for UC.
1. Introduction
Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease characterized by mucosal barrier disruption, immune dysregulation, and excessive epithelial cell death. Current therapeutic options, including aminosalicylates, corticosteroids, and biologics, often achieve only partial remission and are associated with significant adverse effects and high relapse rates. The limited efficacy of existing treatments stems from their inability to address the underlying molecular drivers of epithelial injury, particularly the interplay between defective autophagy and aberrant pyroptosis. Autophagic flux impairment leads to accumulation of damaged mitochondria and reactive oxygen species, which trigger NLRP3 inflammasome activation and subsequent Caspase-1/GSDMD-mediated pyroptosis, perpetuating a vicious cycle of inflammation and tissue damage.
Schisandrin B (Sch B), a bioactive lignan derived from Schisandra chinensis, has demonstrated anti-inflammatory and cytoprotective properties, but its potential to modulate autophagy and pyroptosis in UC remains unexplored. This study employs a TNBS-induced rat model to systematically evaluate Sch B's therapeutic effects and elucidate its mechanism of action. By assessing autophagic flux markers (Beclin-1, LC3-II/I, ATG16L1, p62) and pyroptosis pathway components (NLRP3, Caspase-1, GSDMD), the study aims to establish whether Sch B restores autophagic homeostasis to suppress pyroptosis, thereby providing a mechanistic rationale for its clinical development as a multi-target UC therapy.
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LI Huan, SHI Menghua, WANG Zhixin, YANG Qingyun, GUO Haixia, WANG Jie, ZHANG Shuangxi, AN Yongkang, ZHANG Xiangan (2026). Mechanism of Schisandrin B in Alleviating Pyroptosis of Epithelial Cells in Rats with Ulcerative Colitis Based on Regulation of NLRP3/Caspase-1/GSDMD Signaling Pathway by Autophagy. Chinese Traditional and Herbal Drugs. https://doi.org/10.7501/j.issn.0253-2670.2026.16.20261615
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Frequently Asked Questions
What is the specific dose-response relationship of Sch B in ameliorating UC pathology, and how does it compare to mesalazine?
Sch B was administered at 10, 20, and 50 mg/kg, with significant improvements in DAI, CMDI, and colon length observed at all doses (P<0.05, 0.01). The high-dose group (50 mg/kg) showed effects comparable to mesalazine (100 mg/kg) in reducing inflammatory infiltration and cytokine levels, suggesting dose-dependent efficacy with a favorable therapeutic window.
How does Sch B mechanistically link autophagy restoration to pyroptosis inhibition, and what are the critical molecular checkpoints?
Sch B upregulates Beclin-1 and increases LC3-II/I ratio (P<0.01) while downregulating ATG16L1 and p62 (P<0.05, 0.01), indicating enhanced autophagosome formation and degradation. This restored autophagic flux clears damaged mitochondria, reducing reactive oxygen species that trigger NLRP3 inflammasome activation. Consequently, NLRP3, Caspase-1, and GSDMD expression are downregulated (P<0.05, 0.01), blocking pyroptosis and reducing IL-1β and IL-18 release.
What are the limitations of this study regarding causal inference between autophagy and pyroptosis, and what experiments are needed to validate the mechanism?
The study is limited to in vivo observations without cell-level validation or autophagy blockade rescue experiments. To establish causality, future studies should employ autophagy inhibitors (e.g., 3-MA or chloroquine) in vitro and in vivo to assess whether Sch B's anti-pyroptotic effects are abolished when autophagic flux is blocked. Additionally, genetic knockout models (e.g., ATG16L1 or Beclin-1 knockdown) would clarify the specific autophagy components involved.
What are the translational challenges for developing Sch B as a UC therapeutic, including bioavailability, safety, and manufacturing scalability?
Sch B's oral bioavailability is limited by poor aqueous solubility and first-pass metabolism, necessitating formulation strategies such as nanoparticles or prodrugs. Safety profiles in humans are not yet established, and long-term toxicity studies are required. Manufacturing scalability may be achieved through extraction from Schisandra chinensis or chemical synthesis, but cost parity with mesalazine (approximately $0.50–$2.00 per day) will depend on yield optimization and purification efficiency.
Does Sch B's modulation of autophagy affect other cellular processes that could lead to off-target effects or toxicity?
Autophagy is a ubiquitous process, and systemic activation could potentially alter immune cell function or tumor suppression. However, in this study, Sch B did not cause observable adverse effects in rats over 14 days. Further investigation is needed to assess long-term safety, particularly regarding hepatic and renal function, and to determine whether Sch B selectively targets colonic epithelial cells or exerts systemic effects.
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