Abstract Objective: To investigate the mechanisms underlying the amelioration of metabolic dysfunction-associated steatotic liver disease (MASLD) by hydroxysafflor yellow A (HYA). Materials and Methods: A mouse model of MASLD induced by administration of high-fat high-sugar water (HFSW)-, an oleic acid-palmitic acid (OAPA)-stimulated hepatocyte model, and a hepatocyte-macrophage coculture system were used. Transcriptomic analysis was used to elucidate the function and mechanisms of these models. Results: HYA significantly decreased lipid accumulation, restored fatty acid oxidation, and improved inflammatory responses, thereby alleviating hepatic steatosis in HFSW-fed mice. Furthermore, HYA promoted hepatocyte proliferation and suppressed apoptosis through activation of the viral oncogenic cellular-myelocytomatosis (c-Myc) signaling pathway. It concurrently polarized macrophages toward the M2 anti-inflammatory phenotype and enhanced their lysosomal phagocytic function to clear apoptotic hepatocytes. Conclusions: HYA exerts multifaceted anti-MASLD effects through the coordinated regulation of lipid metabolism and maintaining the balance between apoptosis and proliferation and immune microenvironment homeostasis; thus, HYA is a promising therapeutic candidate for clinical intervention.

Bupleuri radix has demonstrated therapeutic potential in treating liver disorders, and polysaccharides are one of its main bioactive components; however, the effects of Bupleuri radix polysaccharides (BRP) on metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. This study aimed to identify the BRP fractions with anti-MASLD activity and elucidate their underlying mechanisms. We prepared BRP and characterized its physicochemical properties. It markedly alleviated liver injury and restored intestinal barrier function in MASLD. The correlation analysis between transcriptomics and targeted metabolomics showed that BRP restored intestinal acetic acid and propionic acid, with acetic acid activating AMPK and propionic acid promoting cholesterol efflux and metabolism in the liver, thereby reducing lipid accumulation in hepatocytes. Mechanistically, 16S RNA sequencing and diversity analysis indicated that BRP enriched short chain fatty acids (SCFAs)-producing bacteria, such as the genus Muribaculaceae, and inhibited pro-inflammatory microbiota. Interestingly, Paramuribaculum intestinale (P. intestinale), a representative species in the genus Muribaculaceae, synergistically enhanced BRP in improving liver and colonic mucosal damage in MASLD. In conclusion, our findings revealed that BRP improved MASLD by regulating Muribaculaceae-derived SCFAs in the gut-liver axis and could be used in combination with probiotics as a novel therapeutic strategy for MASLD.

ABSTRACT Liver fibrosis is a common pathological process, leading to the development of end‐stage liver diseases. It is triggered by various etiological drivers including viral hepatitis, metabolic‐associated steatotic liver disease (MASLD), and cholestasis. Given the substantial impact of liver fibrosis on individuals and its associated mortality rates, effective management of this condition is crucial for improving public health. Despite a growing number of preclinical studies and clinical trials, a systematic synthesis remains lacking. In this review, the molecular panorama of liver fibrogenesis is summarized at first, encompassing etiological drivers of chronic liver injury, key cellular players, core signaling pathways, and extracellular matrix dynamics. Therapeutic interventions in preclinical or clinical stages are systematically classified into two main categories: etiological treatment as the foundational approach and mechanism‐based antifibrotic therapies. Emerging and future therapeutic strategies, including those targeting gut–liver axis, gut microbiota, and cell‐based therapies, are also addressed along with inherent challenges. Furthermore, future perspectives centered on precision medicine, combination therapies, novel target discovery, and advanced drug delivery systems are emphasized. This review offers a comprehensive overview of the etiologies, diagnostic approaches, pathogenic mechanisms, current development of antifibrotic agents, and prospects for future therapeutic directions of liver fibrosis.

INTRODUCTION:Cholestatic liver disease can progress to advanced stages if left untreated and is lack of effective therapeutic options, highlighting the urgent need for new therapeutic targets. OBJECTIVES:We aim to investigate the involvement of conjugated bile acids and STING signaling in the progression of cholestatic liver diseases. METHODS:We studied cholestatic liver injury in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), as well as in Abcb4-/- mice and in mice subjected to bile duct ligation (BDL). Single-cell RNA sequencing (scRNA-seq) of clinical samples, bulk RNA sequencing (RNA-seq) of isolated primary hepatic cells, and abundant biochemical analysis were analyzed to reveal the damage-response pattern during cholestasis. RESULTS:We found that STING activation was correlated with the severity of liver injuries in patients with PBC and PSC, as well as in BDL and Abcb4-/- mice. Tmem173-/- mice exhibited significant protection against cholestasis-induced ductular reaction, inflammation, and fibrosis. Mechanistically, our results uncovered the cellular heterogeneity of the damage-response pattern during cholestasis. In cholangiocytes, substantial accumulation of conjugated primary bile acids significantly induced mitochondrial damage through the opening of the mitochondrial permeability transition pore, resulting in the production and leakage of oxidized DNA, which facilitates the establishment of senescence-associated secretory phenotype (SASP) by activating STING. The chemoattractive SASP of cholangiocytes then promoted the infiltration and activation of macrophages. Additionally, damage-associated molecular patterns derived from cholangiocytes further triggered the activation of inflammasome and non-lethal pyroptosis in macrophages, which were abrogated by pharmacological or genetic blockade of STING. CONCLUSION:The present study delineates a novel intrahepatic damage-response map during cholestasis and underscores STING signaling as a promising therapeutic target for cholangiopathies.

Hepatic ischemia-reperfusion injury (HIRI) contributes to metabolic disorders within hepatic sinusoid and frequently occurs during liver transplantation, yet its underlying mechanisms and intervention strategies remain obscure. This study aimed to elucidate whether acteoside (ACT) improved HIRI by repairing mitochondrial calcium uptake 1 (MICU1)-mediated Ca2+ dysregulation and facilitating glycolytic reprogramming. Using RNA sequencing, cleavage under targets & tagmentation (CUT&Tag) analysis, liver sinusoidal endothelial cells (LSECs)-specific overexpression virus or siMicu1 lipid nanoparticles and ACT derivatives, we explored the hepatoprotective mechanisms of ACT in vivo in HIRI mice and in vitro in hypoxia-reoxygenation or lactate-stimulated LSECs. ACT enhanced endoplasmic reticulum function and restored mitochondrial homeostasis, thereby alleviating LSECs damage and HIRI. Mechanistically, ACT directly bound to MICU1 and inhibited the overflow of Ca2+ from endoplasmic reticulum (ER) to mitochondria and subsequent mitochondrial Ca2+ overload. This competitive binding mode also suppressed MICU1-dependent glycolysis by blocking Ca2+-stimulated lactate production and histone H3K18 lactylation, which epigenetically regulated MICU1 transcription. Notably, ACT synergized with lactate inhibitors or siMicu1 lipid nanoparticles to enhance its anti-HIRI effects, while LSECs-specific Micu1 overexpression abolished these benefits. Structural analysis revealed that the C26/C27/C40/C41 hydroxyl groups determined ACT's MICU1-binding and hepatoprotective activities. This study identifies MICU1 as a central regulator of HIRI and reveals ACT as a targeted therapy by restoring Ca2+ balance and metabolic homeostasis.

Objective To investigate the therapeutic effects of Sini San (SNS) in cholestatic mice, and to elucidate underlying mechanisms and bioactive ingredients. Methods Through a metabolomics approach, this study identified bioactive components in SNS that were absorbed into the bloodstream. Transcriptomics were performed to identify intrahepatic targets of SNS. Results These findings demonstrated that SNS significantly attenuated partial bile duct ligation (pBDL)-induced cholestatic liver injury by activating intrahepatic peroxisome proliferator-activated receptor alpha (PPARα). SNS-mediated PPARα activation significantly modulated the expression of bile acid transporters to facilitate intrahepatic bile acid homeostasis and simultaneously ameliorates hepatic inflammation. This study identified marmin, astilbin, poncirin, and isosinensetin as potential PPARα agonists among absorbed SNS components. Subsequently, PPARα inhibitor (GW6471) significantly abolished the regulative effects of SNS on lipid and bile acid metabolism. Conclusion This research not only underscores the regulative role of PPARα in bile acid metabolism but also indicates the presence of potential PPARα agonists in SNS, offering a novel therapeutic strategy for treating cholestatic liver disease.

ETHNOPHARMACOLOGICAL RELEVANCE:Si Ni San (SNS) has been used in China for over a thousand years and is widely recognized in other East Asian countries. It has traditional functions of eliminating pathogenic factors and releasing depression (Touxie Jieyu), soothing the liver and regulating Qi (Shugan Liqi). It is widely used in clinical practice for digestive, endocrine, hepatobiliary and mental disorders. AIM OF THIS REVIEW:This review systematically summarizes the traditional uses, modern applications, chemical constituents, and therapeutic effects of SNS based on available literature, and outlines potential directions for future research on SNS. MATERIALS AND METHODS:A comprehensive search was conducted on PubMed, ScienceDirect, and China Knowledge Infrastructure (CNKI) for literature on Sini San published before October 2025. RESULTS:To date, approximately 338 compounds have been identified in SNS, among which paeoniflorin, naringin, glycyrrhizic acid, and saikosaponin A are closely associated with the compositional profile and pharmacological efficacy of SNS and may serve as potential quality markers for this formulation. SNS exhibits a range of pharmacological activities, including hepatoprotective, neuroprotective, gastrointestinal protective, immunomodulatory, anti-inflammatory, antioxidant, antidepressant, and antitumor effects. CONCLUSION:This review provides a comprehensive overview of SNS while critically evaluating the current limitations in SNS research and outlining potential future research directions. SNS and its constituent chemical compounds demonstrate significant potential in hepatoprotection, anti-inflammatory effects, antioxidant activity, and antidepressant properties, offering promising avenues for the development of novel therapeutic strategies and drug discovery.

BACKGROUND:Cholestasis is a common pathological feature in multiple liver diseases which is characterized by toxic bile acid accumulation and liver injury. Emerging evidence indicated that total saikosaponins (TSS) from Radix Bupleuri (RB) could disrupt autophagic flux, probably exacerbating cholestatic liver injuries and warranting further investigation. PURPOSE:This study aims to investigate whether TSS promote cholestatic liver injury by impairing protective autophagy in liver and underlying mechanisms. METHODS:Abcb4-/- mouse was used to evaluate the effects of TSS on cholestatic liver injuries. Bulk RNA sequencing (RNA-seq) of livers was performed to reveal the underlying mechanisms. RESULTS:TSS treatment significantly intensified ductular reaction, inflammation, and fibrosis in Abcb4-/- mice. Mechanistically, excessive taurocholic acid (TCA), the predominantly accumulated-conjugated primary bile acid during cholestasis induced the opening of mitochondrial permeability transition pore (mPTP), leading to the leakage of cytochrome C and DNA from mitochondria in cholangiocytes. By inhibiting autophagosome-lysosome fusion, TSS hindered the clearance and recycling of damaged mitochondria and remarkably enhanced mitochondrial fission. Subsequently, the released DNA-derived from damaged mitochondria drove senescence and senescence-associated secretory phenotype (SASP) in cholangiocytes to promote cholestatic liver injuries. CONCLUSION:Our study demonstrates that TSS exacerbates cholestatic liver injury by suppressing protective autophagy, and engenders a novel therapeutic insight for cholestatic liver diseases by targeting autophagy activation or cholangiocytes senescence. Meanwhile, it underscores the need for heightened clinical caution regarding the use of autophagy-inhibiting medications such as saikosaponins or its analogues in patients with cholestatic liver diseases.

The severe inflammation associated with infectious or inflammatory diseases significantly contributes to mortality. Interferon regulatory factor 3 (IRF3) represents a potential anti-inflammatory target, but the development of IRF3 inhibitors has not yielded satisfactory results to date. In this study, we established a phenotype-based high-throughput screening system to conduct activity-guided hierarchical screening of clinical frequently used anti-inflammatory and anti-rheumatic herbal extracts and compounds. Employing a Gaussia-luciferase reporter system driven by the IFNB1 promoter, we identified sinomenine as a potent type I interferon (IFN) inhibitor from a set of 28 anti-inflammatory herbal products. Furthermore, among 24 synthesized sinomenine derivatives modified by various electrophilic groups, Sim-9 (2.5–10 μM) dose-dependently inhibited IFN responses triggered by TLRs, RLRs, and STING activation in mouse RAW264.7 cells and in human THP-1 cells, HT-29 cells and A549 cells. We demonstrated that Sim-9, by covalently binding to Cys222, induced a conformational change in the pLxIS motif-binding surface of IRF3, thus blocking its interaction with upstream adapters, including TRIF, MAVS and STING, and subsequent homodimerization of IRF3 itself, which were all essential for activation of type I IFN responses. In in vivo experiments, we showed that injection of Sim-9 (30, 60 mg/kg, i.p.) effectively protected against devastating inflammation in cecal ligation and puncture (CLP)-induced sepsis in mice, and improved cerulein-induced pancreatitis by inhibiting IRF3. Our study discovers Sim-9 as a novel covalent allosteric inhibitor of IRF3 and reveals that the pLxIS motif binding surface represents a previously uncharacterized druggable target for IRF3 activation, providing a promising therapeutic strategy for the treatment of severe inflammatory injuries.

Introduction Cholestatic liver diseases are highly prevalent and lack effective treatment, ultimately progressing to end-stage liver diseases. Our recent study indicates that the interplay between c-MYC and lncRNA H19 exacerbates the ductular reaction during cholestasis. Objective: This study aims to unveil the underlying mechanisms of the protective effects of senkyunolide A (SenA) on cholangiocyte overproliferation in cholestatic liver diseases. Methods: Through comprehensive characterization using RNA sequencing, CHIP analysis, protein truncation, amino acid mutation or deletion, and the development of SenA derivatives, we explored the effects and mechanisms of SenA in vivo in bile duct ligation mice and in vitro in primary cholangiocytes. Results: We demonstrated that SenA effectively mitigates cholangiocyte hyperproliferation by epigenetically suppressing c-MYC expression and disrupting the downstream H19, Let-7a and Lin28a. Mechanically, we identified a potential interaction between the carbonyl group in SenA and Arg483 in TRAF6, disrupting the TRAF6-HDAC3 complex. This dissociation facilitates the binding of HDAC3 to the MYC promoter region, resulting in enhanced histone deacetylation and transcriptional suppression. Conclusion: We highlight the therapeutic potential of SenA in cholestatic liver diseases by elucidating its role in epigenetic regulation.

Cholestatic liver disease is characterized by highly accumulated bile acids and cholangiocyte proliferation, resulting in the development of fibrosis, cirrhosis, and ultimately liver failure necessitating liver transplantation. Calcium (Ca2+) signaling is commonly dysregulated in cholestasis and serves as an important regulator mediating cell proliferation. However, the role of Ca2+-mediated cholangiocyte proliferation and treatment strategies in bile duct ligation (BDL)-induced liver injury remains poorly understood. By integrating transcriptomic analysis with molecular biology techniques, we explored the mechanisms of liver injury across BDL animal models, primary cholangiocytes, and human intrahepatic biliary epithelial cholangiocytes. Here, we found that a natural ingredient, senkyunolide A (SenA), effectively alleviated cholestasis-induced Ca2+ release from ER by inhibiting RYR channel, thereby preventing FIP200-mediated ER autophagy in response to Ca2+ transients on the cytosolic ER surface. Increased cytosolic Ca2+ further triggered ER stress, cholangiocyte cycle progression, and ductular reaction (DR). Importantly, SenA reversed the above process through its binding to chloride Channel CLIC Like 1 (CLCC1) for ubiquitination, thereby inhibiting CLCC1 activity and ER Ca2+ release. si-CLCC1-loaded liposomes targeting cholangiocytes enhanced the anti-DR effects of SenA. Collectively, by controlling ER release of Ca2+ in cholangiocytes, SenA presents potential for the development of therapeutic strategies aimed at addressing cholestatic fibrosis.

Background:Sorafenib, a multi-kinase inhibitor, has emerged as a promising therapeutic agent for liver fibrosis due to its ability to target key signaling pathways involved in HSC activation. However, it may inadvertently exacerbate inflammatory responses at certain doses. Recent findings suggest that targeting the STING signaling pathway may provide an alternative strategy for slowing the progression of fibrosis. Methods:We synthesized liver-targeted co-assembled SHG nanoparticles (SHG NPs) that incorporate sorafenib and a hederagenin derivative (Hed), which acted as a STING pathway inhibitor. SHG NPs are preferentially endocytosed by hepatocytes via DSPE-PEG-Gal-mediated ASGPR targeting. After release from hepatocytes, sorafenib diffuses into adjacent HSCs through concentration gradients, effectively inhibiting PDGFR/TGF-β signaling. Hed exhibits dual-targeting characteristics: (1) its STING inhibitory activity selectively acts on macrophage-mediated inflammation; (2) the enhanced phagocytic capacity of Kupffer cells in fibrotic livers promotes non-specific uptake. This spatiotemporal release pattern, combined with pathway-specific pharmacodynamics, ensures synergistic anti-fibrotic effects. Results:In this study, SHG NPs have been successfully formulated with well-defined nanostructures and uniform sizes (115.1 nm). In vitro Sirius Red staining demonstrated that SHG NPs inhibited collagen deposition by 57.5 ± 2.3%, significantly higher than the inhibition observed with sorafenib alone (24.8 ± 1.8%). Furthermore, cell uptake studies confirmed enhanced uptake of SHG NPs in ASGPR-overexpressing cell lines, which was attributed to the presence of galactose on their surface. Additionally, in vivo anti-liver fibrosis activity experiments further confirmed that SHG NPs exhibit superior therapeutic efficacy compared to sorafenib. Conclusion:Our research indicates that formulating sorafenib with a STING pathway inhibitor into liver-targeted nanoparticles represents a potentially effective strategy for the treatment of liver fibrosis.

Introduction Morphological and functional abnormalities of mitochondrial-associated endoplasmic reticulum (ER) membrane (MAM) have emerged as a key mediator of organelle dysfunction during liver fibrosis. Tetramethylpyrazine (TMP) was investigated as a potential therapy for liver fibrosis with an unclear mechanism. Objectives Considering the changes of MAM quantity and gap distance during liver fibrosis, we aimed to investigate the underlying mechanisms and their potential as therapeutic targets for TMP in inhibiting liver fibrosis. Methods Through different sequencing techniques and a series of molecular biology experiments, we explored the effects and mechanisms of TMP in CCl4-induced fibrosis models both in vivo and in vitro and examined key signaling in patients with fibrosis. Results An aberrant increase in the numbers of MAM and drastic alterations in the morphology of ER and mitochondria were accompanied by a substantial influx of Ca2+ from the ER into mitochondria under fibrotic conditions. These changes were largely restored by TMP. Further isolation of distinct cellular fractions revealed that CCl4 caused mis-localization and local concentration of MAM proteins, primarily by suppressing mitofusin 2 (MFN2). TMP directly bound to and stimulated MFN2 expression by activating transcription and inhibiting K79 ubiquitination-mediated degradation, which promoted the interaction and function of MFN2-sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2) complex for reversing Ca2+ overload in mitochondria. Notably, findings in fibrosis patients and hepatic MFN2 knockdown mice further underscored the crucial role of MFN2-mediated normalization of MAM in improving liver fibrosis and the therapeutic effects of TMP. Conclusion Here, we highlight the therapeutic potential of TMP in liver fibrosis by elucidating its role in repairing hepatic MAM.

Inflammatory bowel disease (IBD), a prevalent chronic inflammatory disorder with unsatisfactory therapeutic outcomes, significantly increases the risk of colorectal cancer. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon gene (STING), highly expressed in human IBD, are potential anti-inflammatory and anti-tumor immunotherapeutic targets. However, conflicting evidence regarding the dual roles of the STING pathway has significantly hindered its development as a therapeutic target for innovative treatments. Previous studies have predominantly suggested that hyperactivation of the STING pathway contributes to colitis development, while simultaneously enhancing anti-tumor immunity and inhibiting cancer progression. On the other hand, specific contexts, such as STING deficiency in T cells or prolonged, excessive STING activation within tumors, paradoxically promote disease progression. We also thoroughly analyzed the origin of STING activation in these diseases to offer insights into the identification of novel druggable targets. Crucially, "cell context-dependency, treatment timing and duration, and biased signal transduction" are likely the mechanistic basis underlying STING pathway's dual roles, proposing spatiotemporal-specific STING modulators as future therapeutics.

Background: Liver regeneration is essential for restoring hepatic mass after injury or resection, with metabolic reprogramming as a critical driver. Radix Rehmanniae Praeparata (RRP), a traditional Chinese medicine for chronic liver diseases, regulates glucose and lipid metabolism. This study evaluated the effects of RRP on liver regeneration and explored the underlying mechanisms. Methods: A 70% partial hepatectomy (PHx) mouse model was employed, and integrated transcriptomic and metabolomic analyses were conducted to characterize the global features of RRP-induced metabolic reprogramming and its association with hepatocyte proliferation. To further validate these findings, the AML12 hepatocyte cell line and primary mouse hepatocytes were used to identify key targets of RRP. Results: RRP significantly enhanced liver regeneration, as evidenced by the upregulation of hepatocyte proliferation markers. Transcriptomic, metabolomic, and biochemical analyses showed that RRP promoted lipid catabolism and H3K27ac remodeling-dependent hepatocyte proliferation by increasing acetyl-CoA flux. RRP also enhanced carbohydrate consumption and pentose phosphate pathway, as well as protecting mitochondrial integrity, which contribute to both energy production and nucleotide synthesis during cell cycle progression. Notably, RRP-induced AMPK activation was involved in these metabolic reprogramming events, since pharmacological inhibition of AMPK with Compound C attenuated the promotive effects of RRP on liver regeneration. Conclusions: RRP promotes liver regeneration by enhancing metabolic reprogramming mediated by AMPK activation, highlighting its therapeutic potential for metabolic adaptation and postoperative recovery in compromised liver.

PURPOSE:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Tumor-associated macrophages (TAMs) are key components of the immunosuppressive tumor microenvironment and represent significant obstacles to effective immunotherapy. Phyllanthus emblica L. (PE), a medicinal plant traditionally used in Tibet, has shown therapeutic promise. This study investigates the effects of the tannin fraction of PE (PE-TF) on HCC and its ability to modulate the tumor immunosuppressive microenvironment. METHODS:We evaluated the antitumor efficacy of PE-TF using H22 xenografts and Hepa1-6 orthotopic mouse models. Transcriptomic analysis was performed to identify molecular targets underlying PE-TF suppression of HCC growth. Additionally, UPLC-MS/MS analysis identified the prototypic and metabolic components of PE-TF present in serum, tumor tissues, and adjacent normal liver tissues in the orthotopic HCC model. RESULTS:PE-TF significantly suppressed tumor growth in both subcutaneous and orthotopic HCC models and promoted reprogramming of TAMs toward an antitumor M1 phenotype in vivo. Furthermore, PE-TF counteracted the protumoral effects mediated by bone marrow-derived macrophages (BMDMs) exposed to Hepa1-6-derived conditioned medium (HCM). Although TBH promoted macrophage M2 polarization, the reactive oxygen species (ROS)-scavenging activity of PE-TF effectively inhibited this process. Modulation of the tumor microenvironment by PE-TF-enhanced CD8+T cell infiltration and bolstered their antitumor response, as evidenced by increased transcription of perforin, IFN-γ, and IL-2. Transcriptomic analysis further revealed that T-cell receptor and cytotoxic T-cell signaling pathways are critical mediators of PE-TF' therapeutic effects. Moreover, we preliminarily characterized 79 components across serum, liver, and tumor tissues, and identified metabolic pathways for PE-TF ingredients-including methylation and glycosylation modifications of tumor-enriched constituents. Notably, seven components, such as corilagin and urolithin D, are hypothesized to possess immunomodulatory properties. CONCLUSION:Our findings underscore the potential of PE-TF as an adjuvant immunotherapy for HCC. By scavenging ROS, PE-TF reverses the immunosuppressive M2-TAM phenotype and remodels the tumor microenvironment, thereby enhancing antitumor immunity. Additionally, integrating chemical and metabolic profiling offers a promising strategy for refining candidate selection in future drug discovery endeavors.

The prevalence of depressive-like behavior is significantly higher in patients with cholestatic liver disease, leading to a notable reduction in the quality of life. This situation underscores the urgent need to investigate the mechanisms underlying the association between cholestasis and clinical depression. This review provides a comprehensive examination of how neuroendocrine disorders resulting from cholestasis influence the onset of depression through both direct and indirect mechanisms. First, how the accumulation of bile acids in the central nervous system (CNS) during cholestasis leads to damage to the blood-brain barrier, neuroinflammation, and neurodegeneration is discussed, highlighting the key roles of bile acid receptors, such as FXR and TGR5, in this process. Additionally, the gut-brain axis has been shown to be involved in the development of brain diseases in a variety of ways. Therefore, the indirect indirect effects of bile acids via the gut-brain axis, which affect the composition of the gut microbiota, the integrity of the gut barrier, and the secretion of gut hormones are summarized, thereby regulating the development of depression. However, whether bile acids can directly enter the CNS and which targets are targetable within the gut-brain axis remain pivotal questions. Addressing these issues will open new avenues for developing more effective therapeutic strategies aimed at alleviating depressive symptoms experienced by patients with cholestasis.

When human immune function is compromised,infections caused by pathogenic fungi are often difficult to cure,with invasive fungal diseases frequently associated with high mortality rates.Presently,the types of antifungal drugs available for clinical use are limited,and their toxicity and safety issues can lead to adverse effects for patients.The emergence of drug-resistant strains and the"super fungus"Candida auris has further complicated treatment.Consequently,the identification of new antifungal medications and the formulation of effective combination therapy strategies have emerged as pivotal research priorities within this discipline.Natural products are specialized small molecules that are produced in nature and play pivotal roles in numerous cellular processes and are considered to be among the most significant pharmaceutical agents in the field of human healthcare.Accordingly,the objective of this paper is to review natural products and relevant compounds that exhibit antifungal activity by targeting key components of the fungal cell walls or cell membranes.We focused on the most recent research findings from 2022 to 2025 concerning antifungal natural products derived from plants,fungi,and bacteria,and conducted a comprehensive summary of the sources and types of natural products,along with their antifungal mechanisms of action.Furthermore,we analyzed the application prospects of combining novel natural products with existing antifungal drugs from the perspective of compensatory mechanisms of fungal cell structures,thus establishing new treatment strategies for fungal infections.

Objective Drug-induced liver injury (DILI) is an undesirable reaction caused by drugs, herbal medicines or supplements and may lead to acute liver failure. Polygoni Multiflori Radix (PMR, Heshouwu in Chinese) originated from the roots of Polygonum multiflorum is a popular traditional Chinese medicine (TCM) while potential hepatotoxicity limits its clinical application. The present study aims to elucidate the in-depth mechanism of PMR-induced organelle heterogeneity of hepatotoxicity. Methods Network pharmacology and available TCM transcriptomics databases including Integrated Traditional Chinese Medicine (ITCM) and HERB databases were conducted to identify the active ingredients of PMR with the potent ability to injure organelles including microsome, mitochondria, endoplasmic reticulum (ER), Golgi apparatus (GA), and lysosome. Organelles were isolated and cultured with adenosine triphosphate (ATP)-supplemented system. Western blotting and particle size characterization techniques were further performed to clarify the organelle heterogeneity of PMR-induced hepatotoxicity. Results Five representative organelles were isolated from mouse livers or hepatocytes and administrated with PMR-derived active components and monomers. The results of network pharmacology and virtual screening initially identified the components of PMR that may damage different organelles. By combining experimental verification, we found that five organelles studied in this research were the target organelles for flavonoid (FVN)’s affiliated compound quercetin (QC). Mitochondria were damaged mainly by kaempferol, anthraquinone (AQ) and its monomeric components. Meanwhile, QC and emodin showed effective toxicity on endoplasmic reticulum. For microsome, QC remained the most toxic monomer. For Golgi apparatus, trans-stilbene glycosides (trans-SG), AQ and emodin were the major toxic components in PMR. For lysosomes, total-SG, emodin and QC were the major toxic components in PMR. Conclusion Collectively, our findings revealed the organelle heterogeneity of PMR-induced hepatotoxicity and identified quercetin as a potential toxic component in PMR. This study provides a novel conjunct strategy to screen and discover potential toxic components and shapes the understanding of toxicity warning and clinically safe use of herbal medicines such as PMR.

OBJECTIVE:Ulcerative colitis is closely associated with intestinal stem cell (ISC) loss and impaired intestinal mucus barrier. Sinisan (SNS), a compound Chinese herbal medicine, has a long history in the treatment of intestinal dysfunction, yet whether SNS can relieve acute experimental colitis by modulating ISC proliferation and secretory cell differentiation has not been studied. Our study tested the effect of SNS against acute colitis and focused on the mechanisms involving intestinal barrier recovery. METHODS:Network pharmacology analysis and blood entry component analysis of SNS were used to explore the underlying mechanism by which SNS affects the acute dextran sulfate sodium (DSS)-induced murine colitis model. RNA-sequencing was used to demonstrate the mechanism. Further, reverse transcription-quantitative polymerase chain reaction, immunofluorescence staining, and alcian blue and periodic acid-Schiff staining were performed in vivo and in the colonic organoids to investigate the cell lineage differentiation-related mechanism of SNS. Furthermore, potential active ingredients from SNS were predicted by network pharmacology analysis. RESULTS:SNS dramatically suppressed DSS-induced acute colonic inflammation in mice. RNA-sequencing analysis revealed downregulation of inflammation and apoptosis-related genes, and upregulation of lipid metabolism and proliferation-related genes, such as Irf7, Pparα, Clspn and Hspa5. Additionally, ISC renewal and intestinal secretory cell lineage commitment were significantly promoted by SNS both in vivo and in vitro in colonic organoids, leading to enhanced mucin expression. Furthermore, potential active ingredients from SNS that mediated inflammation, lipid metabolism, proliferation, apoptosis, stem cells and secretory cells were predicted using a network pharmacology approach. CONCLUSION:Our study shed light on the underlying mechanism of SNS in attenuating acute colitis from the perspective of ISC renewal and secretory lineage cell differentiation, suggesting a of novel therapeutic strategy against colitis. Please cite this article as: Cai YJ, Lan JH, Li S, Feng YN, Li FH, Guo MY, et al. Sinisan, a compound Chinese herbal medicine, alleviates acute colitis by facilitating colonic secretory cell lineage commitment and mucin production. J Integr Med. 2025; 23(4): 429-444.