First Affiliated Hospital of Henan University

Primary liver cancer (PLC) is among the most common malignant tumors of the digestive tract, with high incidence and mortality. Hepatocellular carcinoma (HCC) the predominant PLC form has complex pathogenesis. Traditional Chinese medicine (TCM) has gained widespread use as supportive treatment, demonstrating clear efficacy in HCC management. This article summarizes signaling pathways regulating ferroptosis in HCC cells and systematically reviews current research on pathway modulation by TCM active constituents and compound formulas, emphasizing their cytotoxic effects. HCC cellular survival strategies that evade ferroptosis, including hepatic stellate cell-mediated protective mechanisms, are discussed. Clinical limitations of ferroptosis-based treatments and potential solutions are addressed. A comprehensive literature search using PubMed, Embase, Web of Science, and Scopus examined signaling pathways in TCM-mediated ferroptosis in HCC cells. Search terms included "hepatocellular carcinoma," "ferroptosis," "signaling pathway," "traditional Chinese medicine," "TCM monomer," "TCM formula," and "TCM extract," limited to studies from January 2021 to October 2025. Thirty-nine studies were identified: 33 on TCM active ingredients, 1 on TCM extract, and 5 on herbal formulas. TCM active ingredients and formulas promote ferroptosis in HCC cells through modulation of signaling pathways. Pathway modulation inhibits HCC cell proliferation, invasion, and metastasis; promotes apoptosis; increases chemotherapeutic sensitivity; improves glucose metabolism; and reduces drug resistance. TCM can induce ferroptosis in HCC cells through multiple pathways, targets, and mechanisms,highlighting its therapeutic advantages and providing guidance for developing novel ferroptosis inducers.

Global population aging exacerbates the challenges of multimorbidity and polypharmacy in older adults. Clinical practice guidelines are essential for addressing these issues. This systematic review aims to evaluate the quality of existing guidelines and synthesize their recommendations based on the Ariadne principles, to inform future guideline development and clinical practice. We searched nine databases and five guideline repositories (e.g., PubMed, Web of Science, Cochrane Library, CNKI, WHO) up to August 2025. Guidelines and consensus documents focusing on multimorbidity or polypharmacy in older adults, published in English or Chinese, were included. Each guideline was evaluated using four validated tools: AGREE II (methodological quality), RIGHT (reporting completeness), AGREE-REX (recommendation credibility and applicability), and GLIA (implementation feasibility). Recommendations were categorized and synthesized according to the Ariadne principles, with independent screening and data extraction and consensus resolution of discrepancies. The multidimensional appraisal of the 21 included guidelines revealed consistent weaknesses. According to AGREE II, the domains of Scope and Purpose (81.9 %) and Clarity of Presentation (61.1 %) demonstrated the highest median scores, whereas Rigor of Development (16.7 %) and Applicability (8.3 %) scored the lowest. Based on the RIGHT checklist, overall reporting completeness was 43.2 %, with the Evidence (0.0 %) and Quality Assurance (0.0 %) domains being particularly underreported. AGREE-REX evaluation indicated limited implementability at the individual recommendation level (12.5 %), and GLIA, while suggesting moderate implementability at the guideline level (65.4 %), identified frequent barriers in the domains of Measurable Outcomes (100.0 %) and Innovation Requirements (66.7 %). Thematically, most guidelines addressed interaction assessment (n = 15, 71.4 %), but far fewer incorporated patient preferences (n = 9, 42.9 %) or monitoring strategies (n = 9, 42.9 %). Only three guidelines (14.3 %) fully adhered to all five steps of Ariadne principles. Current guidelines for older adults with multimorbidity or polypharmacy exhibit substantial weaknesses in methodological rigor, reporting completeness, and implementation feasibility. Synthesis based on the Ariadne principles revealed an imbalanced pattern of recommendations, with a predominant focus on medication safety rather than patient-centered and longitudinal care management. Future guideline development should strengthen methodological processes, systematically integrate patient perspectives, and co-design practical implementation strategies to better support personalized care for an aging population.

Nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of the global adult population, is a metabolic-associated hepatic disorder characterized by the interplay between inflammation and metabolism. Although evidence linking inflammatory factors and plasma metabolites to NAFLD progression, their causal relationships and mediating mechanisms remain unclear. This study employed a bidirectional Mendelian randomization (MR) approach combined with mediation analysis to investigate the causal relationships between inflammatory factors, plasma metabolites, and NAFLD. Summary data for 91 inflammatory factors and 1400 plasma metabolites were extracted from the genome-wide association studies databases and analyzed using MR. Mediation analysis was performed to examine whether the nine selected metabolites mediated the relationship between the eight inflammatory factors and NAFLD. All the analyses included tests for heterogeneity and pleiotropy. This study identified 11 inflammatory factors and 110 plasma metabolites that were significantly associated with NAFLD. Mediation analysis revealed that specific metabolites, including pregnenetriol disulfate, alanine: asparagine ratio, and X-21471, mediate the relationship between inflammatory factors and NAFLD. Notably, X-21471 was identified as a shared mediator of both tumor necrosis factor receptor superfamily member 9 (TNFRSF9) and CCL20. This integrative MR mediation analysis delineates an inflammation-metabolism-NAFLD axis, in which specific metabolites (X-21471, pregnenetriol disulfate) transmit pro-inflammatory signals (TNFRSF9/CCL20) involved in NAFLD pathogenesis. These findings suggest that combined targeting of TNFRSF9 and X-21471 may represent a precise preventive strategy for high-risk populations with metabolic comorbidities.