Advancing traditional Chinese medicine for sepsis—challenges beyond clinical evidence

The perspective by Ji et al. [1] provides a timely synthesis of evidence for traditional Chinese medicine (TCM) in sepsis management and underscores critical challenges in clinical translation. While the authors comprehensively outline the methodological limitations of existing TCM trials and emphasize the need for high-quality evidence, three interrelated issues warrant further discussion to guide future research and policy: the impact of TCM formulation and delivery routes on clinical outcomes; reconciling methodological rigor with TCM’s holistic principles; and harmonizing quality control with global regulatory standards, additionally, a fundamental question persists: what specific components within validated TCM formulations drive therapeutic effects, and can these components illuminate novel mechanisms of sepsis pathogenesis? 

Ji et al. highlight Xuebijing Injection as a rare example of a TCM preparation validated in a large-scale trial [1]. However, the recent Lancet trial evaluating FYTF-919 (Zhongfeng Xingnao oral prescription) for acute intracerebral hemorrhage—a similarly rigorous multicenter RCT (n = 1640)—demonstrated no benefit compared to placebo [2]. This discrepancy raises questions about whether negative outcomes in TCM trials may partly stem from inappropriate formulation choices (e.g., oral delivery in acute conditions with impaired gastrointestinal absorption) rather than inherent inefficacy. Sepsis trials should prioritize formulations with proven bioavailability for critically ill patients, such as intravenous preparations like Xuebijing, while oral formulations may require pharmacokinetic optimization or biomarker-guided patient stratification [3].

The authors rightly call for multicenter RCTs but do not address tensions between TCM’s personalized “pattern differentiation” principles and the standardized protocols required for regulatory approval. For example, sepsis patients categorized under distinct TCM syndromes (e.g., “toxic heat” vs. “acute deficiency”) may exhibit divergent responses to the same formula [4]. While stratification by TCM syndromes in RCTs could enhance precision, it risks reducing statistical power or increasing heterogeneity. A potential solution lies in adaptive trial designs incorporating syndrome-based subgroups or enrichment strategies guided by biomarkers (e.g., cytokine profiles) that align with TCM’s pathophysiological concepts [5].

Ji et al. note the progress of ISO/TC 249 in establishing TCM quality standards [1]. However, global acceptance of TCM requires not only standardized manufacturing but also transparency in raw material sourcing, batch-to-batch consistency, and stability testing under diverse climatic conditions—challenges exemplified by controversies over heavy metal contamination in herbal products [6]. Regulatory agencies outside China may further demand mechanistic validation of multi-component formulations, as exemplified by the U.S. FDA’s botanical drug development guidelines [7]. Emerging technologies like blockchain for supply chain traceability and AI-driven quality prediction models could bridge these gaps [8]. 

Even when TCM formulations like Xuebijing succeed in RCTs, a critical question remains: which bioactive components mediate therapeutic effects, and do these components reveal unrecognized mechanisms of sepsis? For instance, Xuebijing’s efficacy may arise from synergistic interactions among flavonoids (e.g., baicalin), saponins (e.g., ginsenosides), and polysaccharides, which collectively modulate immune dysregulation, endothelial barrier integrity, and mitochondrial autophagy [9]. This multi-target pharmacology aligns with sepsis’s complexity as a syndrome, where single-target interventions (e.g., anti-TNF-α therapies) have historically failed [10].

Notably, TCM-derived compounds may uncover novel sepsis pathways. Paeoniflorin and other identified constituents in Xuebijing are collectively responsible for the anti-sepsis action [11], validating the “heat-clearing” theory in TCM while implicating metabolic reprogramming in organ injury. Similarly, identifying key active components could reverse-translate to mechanistic discoveries—for example, elucidating how TCM-regulated pathways (e.g., mitophagy crosstalk) inform targeted therapies.

Toward a framework for TCM integration

The path forward demands:

Component-to-mechanism mapping

multi-omics profiling to define core component clusters driving efficacy through host-microbiome-metabolome networks [12].

Reverse translation

advanced organoid models and pharmacological screening to pinpoint TCM targets, revealing sepsis modules (e.g., immune exhaustion, thromboinflammation) [13].

Regulatory innovation

developing “component-target-clinical endpoint” evidence chains compatible with global standards.

While Ji et al. provides a roadmap for TCM evaluation in sepsis, overcoming its global translation barriers requires addressing formulation suitability, harmonizing trial designs with TCM principles, and advancing quality assurance technologies. Crucially, decoding TCM’s bioactive components and their mechanistic insights may bridge empirical practice and precision medicine, offering dual benefits—validating TCM’s role while redefining sepsis pathogenesis.

No datasets were generated or analysed during the current study.

TCM:

Traditional Chinese medicine

FYTF-919:

Zhongfeng Xingnao oral prescription

RCT:

Randomized controlled trial

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Authors and Affiliations

1. Department of Critical Care Medicine, 1st. Affiliated Hospital of Dalian Medical University, Dalian, China

   Wei Huang

2. Department of Medical Affairs, Vantive Health LLC, Shanghai, China

   Minmin Wang

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WH outlined the main concept of this paper, MW wrote the first draft of the manuscript, WH revised it.

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Correspondence to Minmin Wang.

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WH declare to have no competing interests. MW is an employee of Vantive Health LLC. This article is not supported by any company or funding.

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Huang, W., Wang, M. Advancing traditional Chinese medicine for sepsis—challenges beyond clinical evidence. Crit Care 29, 222 (2025). https://doi.org/10.1186/s13054-025-05478-5

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• Received: 27 May 2025

• Accepted: 29 May 2025

• Published: 03 June 2025

• DOI: https://doi.org/10.1186/s13054-025-05478-5

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Keywords

• Traditional Chinese medicine
• Clinical trials
• Drug discovery
• Sepsis
• Xuebijing injection