In recent years, modulation of microglial phenotype transformation has emerged as a promising strategy for treating central nervous system disorders. Aurantii Fructus Immaturus (Zhishi), a traditional Chinese medicine with versatile applications, contains p-Synephrine (p-SYN) as its principal bioactive compound, recognized for its anti-inflammatory efficacy. However, the molecular mechanisms underlying these effects remain unclear. This study aimed to elucidate the mechanisms through which p-SYN modulates the microglial phenotype and alleviates neuroinflammation using both a chronic social defeat stress (CSDS) model and a lipopolysaccharide-induced human microglial cell (HMC-3) system. The antidepressant effects of p-SYN were assessed using various behavioural tests including social interaction, three-chambered social interaction, sucrose preference, tail suspension, forced swimming, open field, and novelty-suppressed feeding tests. Additionally, brain penetration of p-SYN was determined using LC-MS. The results indicated that p-SYN mitigated CSDS-induced social deficits and depressive-like behaviours, and lowered inflammatory responses, as evidenced by decreased levels of TNF-α and IL-6 and increased IL-10 levels. Moreover, p-SYN reduced the expression of M1 markers CD86 and iNOS, while increasing that of M2 markers Arg-1 and CD206. Cellular thermal shift assay, drug affinity reaction target stabilization technology, and co-immunoprecipitation demonstrated that p-SYN directly binds to the 5-hydroxytryptamine 6 receptor (5-HT6R), leading to weakening 5-HT6R and tyrosine kinase FYN interaction and inhibiting the 5-HT6R-FYN-ERK1/2 pathway. This enhances the production of anti-inflammatory factors, subsequently shifts microglia to the M2 phenotype, and eventually mitigates neuroinflammation, thereby exhibiting antidepressant properties.

Hepatic fibrosis (HF) is a pahological consequence of dysregulated wound healing, characterized by excessive deposition of extracellular matrix (ECM) that disrupts liver architecture and function.It is driven by diverse etiologies, including viral, metabolic, cholestatic and toxic insults. Additionally, the pathogenetic mechanisms progressing from initial injury to established fibrosis involve hepatocyte dysfunction, impaired autophagy, oxidative stress, immune modulation, and ultimately the activation of hepatic stellate cells, leading to a sustained imbalance between ECM synthesis and degradation. Consequently, developing effective therapies necessitates strategies targeting both specific etiologies and these core pathological mechanisms.This review systematically examines emerging anti-fibrotic strategies, spanning etiology-specific treatments and inhibitors targeting core pathways (e.g. stellate cell activation, oxidative stress). We evaluate investigational drugs ranging from small molecules and biologics to nano-formulations and highlight multi-targeting natural compounds from Traditional Chinese Medicine (TCM), such as silymarin and resveratrol, which modulate ECM remodeling, inflammation, and metabolism. By integrating preclinical and clinical evidence, this review provides a critical roadmap for developing synergistic therapies that combine modern targeted drugs with natural multi-target agents, addressing a key gap in current research on this integrative approach.

Early-life stress (ELS) was found to increase the risk of adolescent depression, and clinical evidence indicated that eicosapentaenoic acid (EPA) was decreased in patients with adolescent depression, but the underlying mechanisms are unclear. Here, we utilized an ELS model of maternal separation with early weaning to explore the protective role of EPA in adolescent depression. We found that that ELS induced depression-like behavior rather than anxiety-like behavior in adolescent mice. RNA-sequencing results showed that ELS changed the transcription pattern in the liver, including 863 upregulated genes and 971 downregulated genes, especially those related to the biosynthesis of unsaturated fatty acids metabolism in the liver. Moreover, ELS decreased the expression of the rate-limiting enzymes, fatty acid desaturases 1/2 (FADS1/2), involved in the biosynthesis of EPA in the liver. Additionally, ELS reduced the levels of EPA in the liver, serum, and hippocampus, and EPA administration improved depression-like behavior-induced by ELS. Our results provide transcriptomic evidence that ELS increases the risk of adolescent depression by reducing the synthesis of unsaturated fatty acids in the liver, especially EPA, and suggest that supplementation with EPA should be investigated as a potential treatment for adolescent depression.

Psychological distress is associated with an increase in liver disease mortality. This association highlights the close relationship between psychological and physical health. The underlying mechanism of this association needs to be elucidated. In this study, a rat model of anxiety was developed via compound stress. Changes in the HPA axis and inflammatory factors in the brains of the rats were evaluated for behavioral tests and liver function, respectively. The liver metabolic profiles of the rats were characterized through liquid chromatography–mass spectrometry (LC-MS). Differential metabolites were screened based on the conditions of p < 0.05 and VIP > 1. A pathway enrichment analysis was performed on the metabolomics data using the Ingenuity Pathway Analysis (IPA). Immunofluorescence (IF), immunohistochemistry (IHC), and Western blotting assays were performed to examine the expression of the screened target epidermal growth factor receptor (EGFR) and to elucidate the pathway associated with the mechanism. The results showed the impairment of liver function among the rats in an anxiety-like state. Additionally, 61 differential metabolites in the control and anxiety groups were screened using metabolomics (p < 0.05, VIP > 1). The results of the IPA analysis showed that the key target was EGFR. We also found that an anxiety-like state in rats may cause liver injury through the EFGR/PI3K/AKT/NF-κB pathway, which can lead to the production of inflammatory factors in the liver. Our results revealed a mechanism by which anxiety-like behavior leads to liver damage in rats. The findings of this study provided new insights into the deleterious effects of psychological problems on physical health.