Search Results (1,683)

Cutaneous melanoma remains a global health challenge. Although BRAF/MEK-targeted therapies and immune checkpoint inhibitors (ICIs) have improved outcomes in advanced disease, durable responses remain difficult to achieve for most patients. Therapeutic resistance represents the central barrier to long-term disease control. This review comprehensively examines the molecular and immunologic mechanisms underlying melanoma resistance and integrates these insights with emerging pharmaceutical strategies designed to overcome them. We explore the genetic landscape of melanoma, including oncogenic alterations in BRAF, NRAS, NF1, CDKN2A, and PTEN, and explain how dysregulation of the MAPK and PI3K/AKT/mTOR signaling axes drives therapeutic escape. Phenotypic plasticity is discussed as a critical epigenetic driver of drug tolerance. The tumor microenvironment (TME) is examined as an active co-conspirator in resistance, encompassing immunosuppressive cell populations, cancer-associated fibroblasts, and metabolic competition. Resistance mechanisms to targeted therapy, including MAPK reactivation, bypass signaling, transcriptional reprogramming, and metabolic rewiring, are reviewed alongside tumor-intrinsic and tumor-extrinsic mechanisms of ICI resistance. Emerging therapeutic strategies are surveyed, including next-generation RAF and ERK inhibitors, dual-pathway blockade, and metabolic therapies targeting oxidative phosphorylation. Innovations in molecular imaging, liquid biopsy, and artificial intelligence-driven biomarker discovery are highlighted as pivotal tools for real-time resistance monitoring and adaptive treatment. By linking mechanistic insights with translational advances, this review advocates for combination strategies and adaptive clinical frameworks to achieve more durable disease control in melanoma. Full article

Diabetes constitutes one of the major prevailing diseases worldwide, with cardiovascular pathologies as the primary cause of the morbidity and mortality rates reported. Hyperglycemia, the principal hallmark of diabetes, results from accumulated glucose levels. Although molecular mechanisms induced by high glucose (HG) have been extensively investigated, their complex interconnections and immediately activated signaling pathways remain unresolved. Hence, in the present study, we tried to identify effectors directly responsive to HG, focusing on the early activated signal transduction routes in H9c2 cardiac cells. MTT analysis illustrated the apoptosis- and oxidative-stress-mediated detrimental effect of 25 mM glucose on H9c2 viability. Initiation of oxidative-stress-related mechanisms was corroborated via detection of POR and HOX-1 augmented expression levels. Additionally, western blot analysis demonstrated activation of p38-MAPK and ERK1/2, along with autophagy- and ER-stress-related markers. Of note, involvement of biomechanical signaling players was also revealed, with Piezo1, connexin 43 and GJA1-20k expression being gradually enhanced. Intriguingly, ERK1/2 and ER-stress-associated effectors were observed to mediate connexin 43 and GJA1-20k upregulation. With connexins playing a nodal biological role in diabetes-driven cardiovascular pathologies, exploring potential modulatory effectors may provide insight into development of promising therapeutic interventions, favoring preservation of cell function and systems homeostasis under hyperglycemic conditions. Full article

LIM and calponin homology domain-containing protein 1 (LIMCH1) has recently gained attention as a functionally perplexing factor in human cancers, with studies attributing both tumor-suppressive and tumor-promoting properties that defy simple categorization. Originally described as an actin-associated cytoskeletal protein that promotes non-muscle myosin-IIA (NM-IIA) activity and thereby curtails cell migration, LIMCH1 has more recently been linked to diverse oncogenic pathways across a range of tumor types. In lung adenocarcinoma and clear-cell renal cell carcinoma, diminished LIMCH1 expression is associated with more aggressive clinical behavior and reduced overall survival, aligning with a tumor-suppressive role. By comparison, in triple-negative and invasive breast cancers and in cervical squamous cell carcinoma, increased LIMCH1 expression correlates with enhanced metastatic spread, immune escape, and unfavorable outcomes, suggesting a pro-oncogenic function. In this review, findings from over 30 published studies are integrated with an original TCGA pan-cancer expression and survival analysis to propose that LIMCH1 is best understood as a context-dependent conditional regulator rather than as a classical tumor suppressor or oncogene. Based on the available evidence, we propose a hypothesis-generating conceptual framework in which its ultimate phenotypic effect is shaped by three interacting contextual determinants: (i) TP53 mutation status (determining whether the HUWE1-p53 axis is intact); (ii) tumor matrix stiffness (modulating actomyosin contractility and migration mode); and (iii) upstream signaling cues (e.g., MAPK/ERK, TGFβ). Of note, other tumor-lineage and microenvironmental factors may also contribute and warrant further investigation. This framework resolves the apparent functional duality of LIMCH1 in a cancer type-specific manner and provides critical guidance for future mechanistic research, standardized detection workflows, and the clinical translation of LIMCH1-based biomarkers. Full article

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. Despite advances in diagnosis and therapy, the prognosis for advanced HCC remains poor due to late-stage diagnosis, high recurrence rates, therapeutic resistance, and pronounced molecular heterogeneity. HCC development is driven by complex somatic gene alterations, epigenetic reprogramming, dysregulated signaling pathways, metabolic changes, and an immunosuppressive tumor microenvironment. Molecular profiling studies have identified key oncogenic pathways involved in HCC progression, including MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase), Wnt/β-catenin, PI3K/AKT/mTOR (Phosphoinositide 3-kinase/Protein Kinase B/mechanistic Target of Rapamycin), Hippo-YAP/TAZ, (Yes-associated protein/transcriptional co-activator with PDZ-binding motif) cell cycle regulators, and p53-mediated tumor suppression. These pathways coordinate critical cellular processes such as proliferation, survival, metabolism, invasion, and genomic stability. Emerging mechanisms, including cancer stem cell plasticity, immune evasion, epigenetic dysregulation, and steroid receptor coactivator (SRC)-dependent transcriptional regulation, further contribute to tumor progression and therapeutic resistance. Additionally, recent bioinformatic analyses suggest a potential role for progesterone-mediated oocyte maturation pathways in HCC, although their functional relevance remains unclear. A thorough understanding of these interconnected mechanisms could lead to novel therapeutic targets and the development of more effective, personalized treatment strategies for HCC. This review discusses key signaling pathways and emerging mechanisms in HCC and their roles in disease development and treatment. Full article

Background/Objectives: Chronic stress poses a major threat to animal health and welfare, yet current interventions are often invasive, poorly compliant, or lack long-term feasibility. This narrative review synthesizes preclinical mechanistic evidence from mammalian animal models to examine how structured auditory stimulation engages neurotrophic signaling. Structured light music—an auditory stimulus with defined acoustic parameters (e.g., tempo, intensity, and spectral frequency)—has emerged as a promising non-invasive strategy for promoting stress adaptation. However, the molecular mechanism of its effects remains unclear, and systematic analyses linking acoustic features to signaling pathways are scarce. Brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin receptor kinase B (TrkB) constitute a central signaling axis regulating neuroplasticity and stress adaptation, suggesting that this pathway may serve as a critical molecular interface linking auditory stimulation to stress-regulatory processes. Methods: In this review, we focus on structured light music stimuli with distinct acoustic characteristics and examine the molecular mechanisms by which they regulate neural plasticity through the BDNF/TrkB pathway. Results: Existing studies have shown that light music is associated with reversal of stress-induced down-regulation of BDNF/TrkB signaling in the hippocampus and prefrontal cortex. This effect is accompanied by enhanced neurogenesis, dendritic spine remodeling, and synaptic protein synthesis, which are linked to the coordinated activation of three downstream pathways: PI3K/Akt, MAPK/ERK and PLCγ. This cascade reaction further correlates with restoration of negative feedback inhibition of the hypothalamic–pituitary–adrenal axis in the hippocampus, reduces the level of glucocorticoids, and alleviates oxidative stress and inflammatory damage. Conclusions: This review proposes that the BDNF/TrkB pathway may serve as a key molecular basis for light music to regulate neural plasticity and achieve systemic anti-stress effects, and provides new ideas for animal welfare management and the formulation of standardized acoustic intervention strategies. Full article

Inocutis levis (I. levis) is a rare edible and medicinal macrofungus with a traditional history of consumption as a dietary supplement and functional food raw material. However, the material basis and molecular mechanisms underlying its anti-breast cancer activity remain unclear. The present work aimed to systematically investigate the anti-proliferative activity of WYS, an active mycelial fraction isolated from I. levis, against MCF-7 breast cancer cells and to explore its underlying mechanisms. Firstly, 152 metabolites were putatively annotated in the WYS fraction via ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) combined with database matching. Through an integrated strategy combining network pharmacology and multi-algorithm machine learning screening, four core metabolites (dihydroartemisinin, cortisol, cinnamic acid, and guanosine) and five hub targets (CDK1, EGFR, TOP2A, FGF2, and KIT) were prioritized. Furthermore, 100 ns molecular dynamics simulations and molecular docking predicted favorable binding affinities between the core metabolites and their cognate target proteins and predicted that the anti-breast cancer effect of WYS may be associated with the regulation of cell cycle progression, mitochondrial apoptosis, and the MAPK signaling pathway. Subsequent in vitro functional assays validated that WYS inhibited the proliferation of MCF-7 cells in both dose- and time-dependent fashions, triggered G2/M phase arrest and intrinsic mitochondrial apoptosis, and inhibited the EGFR/MEK/ERK signaling axis, exhibiting limited cytotoxicity toward normal HUVEC cells. In vivo, WYS dose-dependently attenuated xenograft tumor growth, and its modulatory effects on cell cycle, apoptosis, and related signaling pathways were consistent with the in vitro observations. This study provides the first evidence that I. levis mycelial fraction WYS modulates EGFR/MEK/ERK-related signaling and induces G2/M cell cycle arrest, thereby exerting anti-proliferative and pro-apoptotic effects on MCF-7 breast cancer cells, providing a scientific basis for further investigation of I. levis as a functional food. Full article

Background: Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland. Although most patients have favorable outcomes, a subset of patients develop aggressive disease characterized by lymph node metastasis and recurrence. Increasing evidence indicates that inflammatory factors participate in tumor progression. However, the expression pattern and functional role of interleukin-1 beta (IL1β) in PTC remain unclear. This study aimed to investigate the expression, biological function, and underlying molecular mechanisms of IL1β in PTC progression. Methods: IL1β expression and its clinical relevance were evaluated using public databases, 152 paired PTC and adjacent non-cancerous tissue samples, and PTC cell lines. Functional assays, including cell proliferation, colony formation, wound-healing, transwell invasion, and flow cytometry assays, were performed to investigate the effects of IL1β on malignant phenotypes. RNA sequencing, proteomic analysis, co-immunoprecipitation assays, rescue experiments, and a xenograft mouse model were conducted to identify and validate the downstream molecular mechanisms of IL1β. Results: IL1β expression was significantly reduced in PTC tissues and cell lines and was negatively associated with lymph node metastasis. Overexpression or recombinant protein treatment of IL1β inhibited PTC cell proliferation, migration, invasion, epithelial–mesenchymal transition, and tumor growth, while promoting apoptosis. Mechanistically, IL1β increased the expression of SMDT1 gene and suppressed MAPK signaling activity by reducing MEK/ERK phosphorylation. Knockdown of SMDT1 gene partially reversed the inhibitory effects of IL1β on PTC cell progression and MAPK pathway activation. Conclusions: This study demonstrates that IL1β functions as a tumor suppressor in PTC through regulation of the SMDT1-MAPK signaling axis. These findings provide new insights into the role of inflammatory regulation in thyroid cancer (THCA) progression and suggest that IL1β-related molecular pathways may represent potential biomarkers or therapeutic targets for aggressive PTC. Full article

Pseudomonas aeruginosa (PA) is a formidable environmental pathogen. It causes severe and refractory bovine mastitis. The escalating threat of antimicrobial resistance requires new non-antibiotic therapies. These alternative therapies should focus on targeting host-directed responses. Sodium butyrate (SB) is a prominent short-chain fatty acid. It possesses potent immunomodulatory properties. However, its protective mechanisms against PA-induced mammary injury remain elusive. This study investigated the efficacy and underlying molecular mechanisms of SB. bMECs were pretreated with 0.5 mmol/L SB for 18 h prior to challenge with P. aeruginosa (1 × 10⁷ CFU/mL, 6 h). We evaluated its ability to alleviate PA-induced cytotoxicity in bovine mammary epithelial cells (bMECs). Flow cytometry and ELISA demonstrated the strong protective effects of SB. SB pretreatment significantly reduced PA-induced cellular apoptosis. It also suppressed the hypersecretion of pro-inflammatory cytokines, including IL-6 and TNF-α. Next, transcriptomic sequencing (RNA-seq) was performed. We identified 589 differentially expressed genes (DEGs) between the PA-challenged and SB-treated groups. These DEGs were significantly enriched in the Toll-like receptor (Tlr), Mapk, and autophagy signaling pathways. We subsequently conducted molecular validations via RT-qPCR, Western blotting, and immunofluorescence. The results revealed that SB significantly suppressed the overactivation of the TLR4/MAPK cascade. Specifically, SB significantly downregulated the expression of TLR4. It also decreased the downstream phosphorylation levels of p38, ERK, and JNK. Furthermore, PA infection induced a severe blockade of autophagic flux. This dysfunction was evidenced by the concurrent cellular accumulation of LC3-II and the autophagic substrate p62. Remarkably, SB intervention was associated with the reduction in autophagic marker accumulation, evidenced by facilitated lysosomal clearance of p62. Collectively, sodium butyrate protects bMECs against PA-induced inflammation and apoptosis. These protective effects are closely associated with the suppression of the TLR4/MAPK signaling cascade and the alleviation of autophagic marker accumulation. This highlights the potential of SB as a promising preventive strategy for the clinical management of bovine mastitis. Full article

Background/Objectives: Repurposing existing drugs may represent a promising strategy for effective cancer therapy. This study was the first to investigate the augmented antitumor therapeutic effect achieved by co-incorporating the NSAID Niflumic acid (NIF) with ceramides into PEGylated cerosomes (NIF-loaded PEG-CERs) in a novel platform that targets specifically the MAPK-ERK signaling pathway and miR-21-5p modulation. Methods: The prepared formulae were statistically optimized utilizing a full factorial design and the optimal formula (C5) was further incorporated into a topical gel and evaluated for ex vivo rat skin permeation, and tested in vivo in a subcutaneous solid Ehrlich carcinoma (SEC) mice model. Results: The optimal formula (C5) showed tubular elongated morphology with higher EE% (96.71 ± 0.0), lower vesicular size (VS) and PDI values, 292.95 ± 0.78 nm and 0.47 ± 0.0 respectively. A high ZP value (−37.5 ± 0.57 mV) was in accordance with stability results showing good stability of the optimal formula (C5). Permeability studies exhibited 2.02-fold higher skin permeation compared to pure NIF gel. A significant decrease in tumor volume and marked improvement in survival rate in SEC mice were confirmed by downregulation of EGFR, ERK1, ERK2, and miR-21-5p expression. Furthermore, an increase in total antioxidant capacity and caspase-3 levels was observed, accompanied by significant suppression in cyclin D1, MMP-2, COX-2, and MDA levels. Finally, histopathological analysis revealed the superior antitumor effect of C5 gel together with immunohistochemical assay showing the lowest BCL-2-positive staining, indicating the restoration of physiological apoptotic balance. Conclusions: Based on the previous findings, NIF-loaded PEG-CERs offer augmented therapeutic potential for efficient topical skin cancer management in an SEC mice model. Full article

Bioactive polyphenols have emerged as multi-target regulators of cellular processes involved in the pathogenesis of skin diseases. Skin disorders, including inflammatory conditions, photoaging, and skin cancers, are characterized by complex pathogenic mechanisms associated with oxidative stress, mitochondrial dysfunction, dysregulated signaling pathways, and metabolic imbalance. Excessive production of reactive oxygen species (ROS) and persistent inflammatory signaling contribute to disease progression and cellular adaptation under stress conditions. Unlike conventional agents that typically target a single pathway, polyphenols act on interconnected signaling and metabolic networks. These compounds regulate key signaling pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), AMP-activated protein kinase (AMPK), nuclear factor-κB (NF-κB), and nuclear factor erythroid 2-related factor 2 (Nrf2), thereby regulating cell survival, proliferation, inflammatory responses, antioxidant defense, and metabolic adaptation. Polyphenols also influence mitochondrial function by maintaining redox homeostasis, regulating energy metabolism, and affecting apoptosis-related signaling pathways. This review provides a mechanistic overview of the effects of polyphenols on oxidative stress, mitochondrial function, and cell survival signaling in skin diseases. In addition, the therapeutic implications and current limitations of polyphenol-based approaches are discussed, with particular emphasis on the translational gap between experimental findings and physiological relevance. Factors such as concentration, bioavailability, and cellular microenvironment are highlighted as major determinants of polyphenol activity and key challenges for clinical translation. Finally, the need for further in vivo and clinical investigations is emphasized to support the development of effective polyphenol-based therapeutic strategies for skin diseases. Full article

Non-small-cell lung cancer (NSCLC) treatment is hampered by its complex pathogenesis and high heterogeneity. N6-methyladenosine (m⁶A) represents the most common post-transcriptional modification regulating RNA stability and function in eukaryotes. This methylation is catalyzed by methyltransferase complexes, with METTL14 being the core catalytic subunit. Abnormal expression of lncRNA MSTRG.292666.16 is related to poor prognosis of NSCLC. However, the mechanism by which it regulates NSCLC progression through m⁶A modification remains unclear. We employed cell function experiments, molecular mechanism analysis, RNA interaction experiments, and a nude mouse tumor model to explore the roles of METTL14-mediated MSTRG.292666.16 m⁶A modification in NSCLC and the potential MAPK signaling pathway involved. METTL14 was significantly upregulated in NSCLC cell lines and promoted m⁶A modification of MSTRG.292666.16 by forming a stable association with it. METTL14 knockdown significantly inhibited the viability, migration and invasion of A549 cells and promoted apoptosis, whereas MSTRG.292666.16 overexpression reversed these effects. Mechanistically, METTL14 upregulated the expression of MSTRG.292666.16 through m⁶A modification, thereby activating the MAPK pathway (manifested as elevated levels of MAPK8IP3 and p-ERK1/2). The use of a selective p38 MAPK inhibitor SB203580 stimulated the tumor-suppressive effect of METTL14 knockdown, whereas the activator U-46619 reversed it. In vivo experiments confirmed that METTL14 knockdown significantly inhibited tumor growth, whereas MSTRG.292666.16 overexpression partially restored the malignant phenotype of the tumor, which was associated with MAPK pathway activation. This study revealed that METTL14-dependent m⁶A modification of MSTRG.292666.16 may act as an upstream driver to activate the MAPK cascade and facilitate NSCLC progression. These findings clarify a key epitranscriptomic regulatory mechanism driving NSCLC development and offer preliminary molecular clues for exploring potential therapeutic targets in subsequent clinical NSCLC research. Full article

Background: Primary dysmenorrhea (PD) is a prevalent gynecological condition that significantly compromises the quality of life in adolescents and women of reproductive age. Within traditional Chinese medicine (TCM), Cold Coagulation and Blood Stasis Primary Dysmenorrhea (CCBS-PD) represents the most frequently observed syndrome pattern of PD. Wenjing Decoction (WJD), a classical TCM formulation, has been extensively employed for the treatment of CCBS-PD. However, given the multi-component and complex nature of WJD, the potential mechanisms underpinning its therapeutic effect have yet to be elucidated. Methods: A rat model of CCBS-PD was induced through ice-water bath stimulation in conjunction with estradiol benzoate and oxytocin. The pharmacological effects of WJD were evaluated by writhing response, hemorheological parameters, uterine index, histopathological examination, and biochemical assays. Serum-exposed constituents of WJD were characterized using UPLC-Orbitrap Exploris 120 MS. To study the mechanisms of WJD, methods from network pharmacology, molecular docking, and off-target metabolomics were used. Western blot analysis examined representative proteins in the signaling pathways predicted by network pharmacology. Network pharmacology and metabolomics were integrated to construct a pathway–metabolite–target–compound network, and representative targets were analyzed by RT-qPCR. Results: WJD treatment reduced writhing responses, improved hemorheological abnormalities, and alleviated uterine pathological changes in CCBS-PD rats. Serum pharmacochemistry identified 62 WJD-derived constituents. Metabolomics analysis indicated that WJD was associated with alterations in nitrogen metabolism, valine/leucine/isoleucine biosynthesis and arginine biosynthesis. Network pharmacology and molecular docking suggested several candidate compounds and targets, including Robinetin, Levistolide A, Pratol, 7,4′-dihydroxyflavone, EGFR, AKT1, ESR1, MMP9, MAPK3, and TNF. RT-qPCR showed that selected genes, including AKT1, EGFR, MAPK3, TNF, ESR1, MMP9 and CASP3, were changed in the model group and partially restored following WJD improvement. Western blot analysis demonstrated that WJD treatment decreased the phosphorylation levels of AKT, ERK1/2, and NF-κB, and down-regulated the protein expression of COX-2. Conclusions: WJD showed beneficial effects in a CCBS-PD rat model. Synthesized assessments indicate a potential link to the actions of serum-exposed constituents, alterations in amino acid metabolism, and modulation of inflammation-related signaling pathways. This research offers initial indications suggesting the multi-component and multi-target pharmacological actions of WJD, although the underlying mechanisms remain to be validated through targeted metabolomics and functional studies. Full article

Cannabinoids are terpenophenolic compounds derived from Cannabis sativa L. that exert a broad range of biological and pharmacological activities. Increasing evidence highlights their potential as modulators of cancer progression specifically through the suppression of tumor cell growth, angiogenesis, and metastasis across multiple tumor models. This review provides a comprehensive overview of the molecular mechanisms by which natural and synthetic cannabinoids induce regulated cancer cell death. Current evidence demonstrates that cannabinoids regulate multiple forms of cancer cell death, including apoptosis, autophagy-dependent cell death, necroptosis, ferroptosis, and parthanatos. These effects are mediated through complex and interconnected signaling pathways such as TRIB3/AKT/mTORC1, PI3K/AKT/mTOR, MAPK/ERK, NF-κB, ERK/JNK/p38-MAPK, and ceramide/Raf1/ERK/ROS. In addition to their direct antitumor effects, cannabinoids can enhance the efficacy of conventional anticancer therapies through the coordinated regulation of complementary cell death pathways. They also provide clinically relevant supportive benefits in palliative care, alleviating chemotherapy-induced nausea, cachexia, and mood or sleep disturbances. Collectively, these findings identify cannabinoids as promising anticancer agents and therapeutic adjuvants, predominantly in the preclinical setting. However, significant challenges remain regarding their safety, optimal dosing, formulation, and clinical efficacy. Further mechanistic studies, rigorous preclinical research, and well-designed clinical trials are required to establish the translation of cannabinoid-based therapies into precision oncology. Full article

Skin pigmentation is regulated by intrinsic and extrinsic factors and is closely associated with melanogenesis and cellular homeostasis. Autophagy is a cellular self-digestion process that contributes to homeostatic regulation, but its role in melanogenesis remains to be further clarified. This study investigated whether berberine chloride (BBC), an isoquinoline alkaloid, modulates melanin production through autophagy-related signaling in B16-F1 melanoma cells. Tyrosinase activity was examined by tyrosinase zymography, extracellular melanin levels in the culture supernatant were measured after BBC treatment, and the expression of melanogenesis-, mitogen-activated protein kinase (MAPK)-, and autophagy-related proteins was analyzed by Western blotting. BBC inhibited tyrosinase activity and reduced extracellular melanin levels in a dose-dependent manner. BBC also increased phosphorylated extracellular signal-regulated kinase (p-ERK) levels while decreasing melanogenesis-related protein expression. In addition, BBC modulated MAPK signaling and the expression of autophagy-associated proteins. Small interfering RNA-mediated knockdown of Atg5, Beclin1, or ERK partially restored extracellular melanin levels in BBC-treated cells. These findings suggest that BBC suppresses melanogenesis in B16-F1 melanoma cells in association with ERK and autophagy-related signaling. Full article

Objectives: This study focuses on exploring the mechanism by which Schisandrin B (Sch B) regulates metabolic dysfunction-associated steatotic liver disease (MASLD) mice induced by a high-fat methionine–choline-deficient (MCD) diet through the activation of peroxisome proliferator-activated receptor γ (PPARγ). Methods: Male C57BL/6 mice were fed a high-fat MCD diet for 8 weeks to establish a mouse MASLD model, and the effects of Sch B on MASLD and the mechanisms were investigated. PPARγ overexpression (OE) was induced by adeno-associated virus (AAV) administration via intrahepatic portal vein injection in mice, and a negative control (NC-OE) was also established. Body weight; wet liver weight; hepatic index; serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β); and hepatic triglyceride (TG) levels were measured in the mice. The histopathology and lipid deposition were observed by hematoxylin and eosin (H&E) staining and Oil Red O staining, while the fibrosis was assessed using Masson staining. Western blot was employed to detect the expression levels of PPARγ, sterol regulatory element-binding protein 1c (SREBP-1c), carnitine palmitoyltransferase 1A (CPT1A), transforming growth factor β1 (TGF-β1), α-smooth muscle actin (α-SMA), collagen type I (collagen I), Smad family members 2/3 (Smad2/3), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase 1/2 (ERK1/2), along with the phosphorylation activation status of these kinases. Results: It was confirmed that Sch B caused effects similar to those induced by PPARγ overexpression, reducing the hepatic index, AST, and ALT levels while alleviating lipid accumulation and fibrosis; and upregulating PPARγ and CPT1A while inhibiting SREBP-1c; and the phosphorylation of the TGF-β/Smad and MAPK pathways were involved in the mechanisms. Conclusions: Sch B can alleviate high-fat MCD-induced MASLD by activating PPARγ in mice. Full article