Hydrogen peroxide pathway in ulcerative colitis: Promises and challenges in translating novel pathogenesis to clinical practice

Table 1 Comparison of pathological mechanisms and treatment methods between the new hypothesis and traditional theories of ulcerative colitis

Mechanism	H2O2 hypothesis	Traditional treatment
Root cause	Excessive H2O2 production and accumulation in colonic epithelial cells	Abnormal activation or dysregulation of the immune system[17]
Initial event	Mitochondrial H2O2 generation increased - intracellular accumulation - transmembrane diffusion	Aberrant T-cell activation - cytokine release[18]
Neutrophil recruitment	Direct chemotactic effect of H2O2	IL-8, CXCL1, and other chemokine-mediated recruitment[19]
Inflammatory cascade	H2O2 - neutrophil infiltration - tissue damage - additional H2O2 release	Th1/Th17 activation - TNF-α/IL-17 increased - inflammatory amplification[20]
Tissue damage mechanism	H2O2-mediated disruption of tight junction proteins - epithelial barrier dysfunction	Cytotoxic T cells and NK cell-mediated epithelial cell killing[21]
Primary drugs	STS, R-DHLA	Mesalazine, biologics, immunosuppressants, JAK inhibitors[22]
Drug action	H2O2 neutralization (extracellular and intracellular)	Anti-inflammatory, immunosuppression

CXCL1: Chemokine CXC ligand 1; H₂O₂: Hydrogen peroxide; IL: Interleukin; JAK: Janus kinase; LPS: Lipopolysaccharide; NK: Natural killer; R-DHLA: R-Dihydrolipoic acid; STS: Sodium thiosulfate; TNF: Tumor necrosis factor.

Table 2 Phase 2 randomized controlled trial design for mild to moderate active ulcerative colitis

Design requirements	Specific protocol	Key considerations
Study design	Multicenter, randomized, double-blind, placebo-controlled phase 2 trial	Compliance with ICH-GCP standards
Target population	Patients with mild to moderate active UC (PRO2 score 2-5 points)	Balance baseline risk; standardize severity assessment
Inclusion criteria	Age 18-65 yr; MES score 1-2 points; discontinue biologics ≥ 8 wk	Exclude severe UC and active infectious diseases
Sample size	180 subjects (90 per group)	80% statistical power; anticipated 15% dropout rate[23]
Randomization design	1:1 randomized allocation by disease severity stratification	Ensure balanced baseline characteristics and reduce bias
Treatment groups	Group A: 5-ASA + STS (extracellular H2O2 scavenger); Group B: 5-ASA + placebo	Specific dosing regimens determined through phase 1 dose-escalation studies
Biomarker assessments	Weeks 0, 4, 8, 12: CRP, fecal calprotectin, neutrophil count, serum 8-isoprostane F2α, malondialdehyde, GPx activity	Based on STRIDE-II criteria[24]; combined oxidative stress biomarkers
Primary endpoint	Clinical response rate at week 12 (PRO2 score reduction ≥ 50%)	Meets STRIDE-II recommended patient-reported outcome measures
Key secondary endpoints	Clinical remission, endoscopic response, histological improvement, oxidative stress biomarker changes at week 12	Endoscopic response: MES ≤ 1 point; Histological improvement: Geboes score < 2.0
Safety assessment	Liver and kidney function tests at Weeks 0, 4, 8, 12; document and evaluate adverse events at each visit	Balance safety monitoring requirements with patient convenience
Follow-up plan	Treatment period: 12 wk + long-term follow-up to 52 wk	Evaluate long-term efficacy maintenance and safety

UC: Ulcerative colitis; ICH-GCP: International Council for Harmonisation-Good Clinical Practice; MES: Mayo Endoscopic Score; PRO2: Patient-Reported Outcome 2; 5-ASA: 5-aminosalicylic acid; GPx: Glutathione peroxidase; STRIDE-II: Selecting Therapeutic Targets in Inflammatory Bowel Disease Initiative update; CRP: C-reactive protein.