Drug-induced liver injury (DILI) is a global health concern and one of the leading causes for the withdrawal of drugs from the market. DILI can exacerbate chronic liver injury to acute or chronic liver failure. The mitogen-activated protein kinase (MAPK) signaling cascade is the most conserved pathway that regulates key physiological processes, including cell proliferation, differentiation, inflammation, stress responses, and apoptosis. MAPK pathways such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 are activated by growth factors, cytokines and oxidative stress-related signaling. Increasing evidence indicates that drug metabolism-induced reactive oxygen species (ROS) can activate MAPK pathways such as ERK, JNK, and p38 MAPK in hepatocytes. Activation of MAPK through phosphorylation contributes to necrosis and apoptosis, mitochondrial toxicity, oxidative stress, inflammation, and impaired autophagy. MAPK activation can also stimulate nuclear factor-κB (NF-κB)-mediated inflammatory signaling, thereby amplifying liver injury. While the role of MAPK signaling in acetaminophen-induced hepatotoxicity is well established, emerging studies indicate that several classes of drugs can also trigger MAPK-mediated liver injury. In this context, the present review aimed to summarize the current understanding of MAPK signaling pathways involved in the pathogenesis of DILI, emphasis the roles of ERK, JNK, and p38 pathways in mediating oxidative stress, inflammation, and hepatocyte death. Understanding these mechanisms may help identify potential therapeutic targets and guide future clinical strategies for the prevention and management of DILI.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high morbidity and mortality worldwide. Its etiology is complex, involving multiple aspects such as viral infection, dietary exposure, chemical pollution, lifestyle and endogenous factors. This review conducted a comprehensive search in databases such as PubMed and Scopus using keywords including “hepatocellular carcinoma”, “environmental factors”, “epidemiological trends”, and “prevention and treatment strategies”. Relevant papers, including clinical case reports, reviews, and basic research, were included. This study systematically reviewed the mechanisms and epidemiological characteristics of external environmental factors such as viral infection, aflatoxin, arsenic, vinyl chloride, per- and polyfluoroalkyl substances, microplastics, oral contraceptives, nitrite, and microcystin-leucine arginine in the occurrence of HCC; internal environmental factors such as genetic susceptibility, diabetes, obesity, metabolic dysfunction-associated steatotic liver disease, metabolic syndrome, gut microbiota, and sex hormones; other factors such as alcohol consumption, smoking, insufficient sleep, lack of exercise and aging. A variety of preventive and intervention measures have been proposed, including hepatitis B vaccination, reduction of aflatoxin and alcohol exposure, tobacco control, antioxidant supplementation, regular rest and exercise. The prevention and control of HCC should range from infectious disease prevention and control to metabolic disease management and environmental governance, combined with individualized risk assessment and precise prevention strategies.
Hepatocellular carcinoma (HCC) is a common and lethal malignancy, with an increasing incidence globally, which is partially attributed to the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Complex metabolic rearrangements occur in MASLD-related HCC (MASLD-HCC) to promote the initiation and development of cancer. Nevertheless, comprehensive understanding of the metabolic transformations during the progression from MASLD to HCC remains limited. In this review, we introduce recent advances characterizing the metabolic changes in MASLD-HCC, thereby offering potential directions and clues for further studies.
BACKGROUND:Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy, and its intrinsic variability contributes to aggressive progression, recurrence, and therapeutic resistance. Exosomes are key mediators of intercellular communication among tumor cells with different malignant potentials, while N6-methyladenosine (m6A) modification has emerged as a critical epigenetic regulator of tumorigenesis. However, the mechanisms by which exosome-mediated m6A regulation contributes to HCC progression and heterogeneity remain poorly understood. METHODS:Exosomal microRNA (miRNA) profiles from HCC cells with distinct malignant phenotypes were analyzed using microarray analysis, and the clinical relevance of miR-769-3p was evaluated in samples of HCC patients. Gain- and loss-of-function assays were performed to assess its effects on HCC proliferation and metastasis both in vitro and in vivo. AlkB homolog 5 (ALKBH5) was identified as a downstream target of miR-769-3p, and its m6A-dependent regulatory mechanism was investigated using methylated RNA immunoprecipitation sequencing and subsequent validation assays. In addition, a liposome-based drug delivery system targeting miR-769-3p was developed and evaluated for therapeutic efficacy. RESULTS:Exosomal miR-769-3p was significantly enriched in highly malignant HCC cells and was associated with poor clinical outcomes. Functional studies demonstrated that exosomal miR-769-3p promoted HCC proliferation and metastasis by suppressing ALKBH5 expression. Mechanistically, ALKBH5 inhibited the expression of the oncogene G protein subunit alpha z (GNAZ) in an m6A-dependent manner, while ALKBH5-mediated destabilization of GNAZ transcripts required the m6A reader insulin-like growth factor 2 mRNA-binding protein 1. Importantly, in vivo experiments revealed that a liposomal delivery system targeting miR-769-3p markedly suppressed HCC tumor growth and metastatic dissemination. CONCLUSIONS:Exosomal miR-769-3p mediates malignant intercellular communication between HCC subtypes by regulating the ALKBH5/m6A/GNAZ axis. Targeting miR-769-3p using a liposome-based delivery strategy represents a promising therapeutic approach for HCC. These findings provide novel mechanistic insights into HCC progression and identify a potential therapeutic target for HCC treatment.
BACKGROUND:Biliary tract cancer (BTC) has a high postoperative recurrence rate and limiting long-term survival. Accurate prediction of recurrence is vital for clinical management. Carbohydrate antigen 19-9 (CA19-9) and the neutrophil percentage-to-albumin ratio (NPAR) are established prognostic markers in various cancers, but their combined value in BTC remains unclear. This study assessed the predictive role of the combination of CA19-9 and NPAR on time to recurrence (TTR) and introduced the novel NPAR-CA19-9 stratified score (NCSS). METHODS:A total of 145 BTC patients who underwent resection between March 2019 and December 2023 were analyzed. Preoperative blood samples, collected within two weeks of surgery, were used to measure CA19-9 and NPAR. Cutoff values were defined using the Maximum Selected Rank Statistic (MSRS). NCSS (0-2) were assigned according to marker levels and evaluated using Kaplan-Meier survival analysis and Cox regression models. RESULTS:Higher NCSS were associated with shorter TTR and reduced overall survival (P < 0.001). Cox regression confirmed NCSS as an independent predictor of recurrence [NCSS = 1: hazard ratio (HR) = 1.82, 95% confidence interval (CI): 1.05-3.14; NCSS = 2: HR = 2.95, 95% CI: 1.54-5.64] and overall survival (NCSS = 1: HR = 5.21, 95% CI: 1.19-22.82; NCSS = 2: HR = 11.88, 95% CI: 2.44-57.75). Subgroup analysis showed that patients with NCSS = 1 or 2 benefited from adjuvant chemotherapy, whereas those with NCSS = 0 did not. Incorporating NCSS into a nomogram improved prediction of TTR compared with a model excluding NCSS (C-index: 0.72 vs. 0.70; P = 0.027). CONCLUSIONS:NCSS is a novel, simple, and effective preoperative scoring system that predicts TTR and overall survival in BTC patients, supporting more individualized treatment planning.
Background The incidence and mortality rates of metabolic dysfunction-associated fatty liver disease (MAFLD) have been steadily increasing. Lactylation, a post-translational modification, has been implicated in lipid metabolism disorders. This study aimed to investigate the role of lactylation in the development of MAFLD and to elucidate the underlying mechanisms. Methods The relationship between lactate, lactylation, and MAFLD was explored using clinical MAFLD samples from First People’s Hospital of Kunming City between March 2021 and September 2024. Proteomic sequencing of these samples was performed, and key proteins were identified by intersecting differentially expressed proteins in MAFLD with differentially modified lactylation sites. Subsequently, an in vitro cellular model of MAFLD was established. The involvement of the key gene methyl-CpG-binding protein 2 (MeCP2) in the MAFLD-lactylation mechanism was assessed using various techniques, including the CCK-8 assay, Oil Red O staining, Bodipy 493/503 fluorescence staining, Western blot, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and co-immunoprecipitation (CO-IP). Results The key gene MeCP2 was identified by intersecting differentially expressed proteins in MAFLD with lactylation-modified proteins. In MAFLD liver tissue, we observed lactate accumulation, increased lactylation, and elevated MeCP2 expression. In the in vitro MAFLD cell model, lactate was found to promote lactylation, increase MeCP2 expression, and facilitate progression in a dose-dependent manner. Interference with MeCP2 expression inhibited acetyl-CoA carboxylase/fatty acid synthase (ACC/FAS)-mediated lipogenesis while enhancing peroxisome proliferator-activated receptor-α (PPARα)-mediated lipid oxidation. Furthermore, MeCP2 was found to interact with the lactylation-associated protein pan-Kla. Inhibition of MeCP2 suppressed lipid formation by reducing lactylation, thus ameliorating the progression of MAFLD. Conclusions Targeting MeCP2 expression improves the pathophysiology of MAFLD by downregulating lactylation, inhibiting ACC/FAS-mediated lipid synthesis, and promoting PPARα-mediated lipid oxidation.
BACKGROUND:Pancreatic tuberculosis is a rare entity. Most cases of pancreatic tuberculosis are documented in case reports. There has been no systematic analysis of the imaging characteristics of pancreatic tuberculosis, its association with abutting peripancreatic tuberculous lymphadenopathy, and its likely pathogenesis. DATA SOURCES:A comprehensive search of pancreatic tuberculosis literature was conducted in MEDLINE, Embase and Scopus from 1978 to 2024. Manual searches of references in the published literature were also performed. The inclusion criteria for eligible cases comprised patient demographics, symptoms, imaging, pathology, microbiology, treatment and outcomes. RESULTS:A total of 252 eligible patients with pancreatic tuberculosis were identified, including 8 (3.2%) associated with miliary tuberculosis and 244 (96.8%) associated with non-miliary tuberculosis. Because the pathogenesis of miliary tuberculosis was distinct and hematogenous dissemination, only the 244 non-miliary tuberculosis patients were analyzed. Among these 244 patients, 61.5% were diagnosed in Asia and 69.2% younger than 50 years. The common symptoms were epigastric pain (79.5%) and weight loss (57.4%). In 244 patients, the most common imaging finding was a solitary mass (94.3%), with 84.8% occurring in the pancreatic head/uncinate process. The predominant imaging findings were heterogeneous lesions with ill-defined borders (77.7%), intralesional hypoechoic/anechoic areas on ultrasound (84.8%), and intralesional low-attenuation areas on contrast-enhanced computed tomography (CT) (86.4%). Peripancreatic tuberculous lymphadenopathies abutting pancreatic tuberculous lesion were observed in 89.3% of 244 patients. Pancreatic tuberculous lesions closely associated with peripancreatic abutting lymphadenopathy, observed in 198 (81.1%) patients. Among 95 patients who underwent surgery, 59 were found to be directly derived from their abutting lymphadenopathies. CONCLUSIONS:Only a small proportion of patients with pancreatic tuberculosis are related to miliary tuberculosis. Pancreatic tuberculosis is more likely to originate from peripancreatic tuberculous lymphadenitis.
Liver cancer, primarily hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is a growing global health concern. The widespread administration of hepatitis B vaccines has reduced the incidence of virus-associated liver cancer, but the rise in nonviral-related cases remains overlooked. Water pollutants, as critical environmental carcinogens, may contribute significantly to the increase in cases by acting as potential etiological agents. This review summarized the literature up to March 2025 on PubMed and drew conclusions regarding the roles and mechanisms of water pollutants in liver cancer initiation and progression. Inorganic contaminants, such as heavy metals, arsenic, and nitrates, can trigger a cascade of liver injury, gene mutations, precancerous lesions, and ultimately cancer. Similarly, organic pollutants, including organochlorine pesticides, flame retardants, per- and polyfluoroalkyl substances, and cyanobacterial toxins, promote liver cancer through diverse molecular pathways. To counter the increasing burden of nonviral liver cancer, there is an urgent need to establish efficient pollutant monitoring systems and optimize intervention strategies to mitigate the global liver cancer burden.
BACKGROUND:Neoadjuvant therapy (NAT) is increasingly used among patients with pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC commonly present with sarcopenia, which may progress during the period of NAT and subsequently impact treatment outcomes. However, data assessing trends in sarcopenia are currently lacking. As such, this audit sought to quantify changes in body composition during NAT, and to assess whether these correlated with patient outcomes or pancreatic enzyme replacement therapy (PERT) usage. METHODS:Computed tomography (CT) scans performed pre- and post-NAT were analyzed to assess measures of sarcopenia, namely the psoas muscle index (PMI) and intramuscular adipose content of the multifidus (IMAC; a proxy for muscle function), and measures of adiposity, namely the cross-sectional areas of subcutaneous adipose tissue and visceral adipose tissue (SAT/VAT). Associations between the changes in these measures and surgical resection rates, survival and PERT usage were then assessed. RESULTS:Among 100 patients receiving NAT, all four measures of body composition were found to be decreased significantly between the pre- and post-NAT CT scans, with these reductions being significantly greater in patients who did not subsequently undergo surgical resection. In patients undergoing resection, larger reductions in PMI (P = 0.007) and SAT (P = 0.043) were associated with significantly shorter survival. PERT was associated with significantly smaller reductions in PMI (mean: 0.50 vs. 0.89 cm2/m2, P = 0.046), as well as significantly longer survival in resected patients (hazard ratio: 0.47, 95% CI: 0.22-0.98, P = 0.045). CONCLUSIONS:This audit demonstrates that the progression of sarcopenia during NAT, which could preclude surgical resection of PDAC, is a crucial prognostic factor for survival in this setting. PERT may mitigate sarcopenia progression and improve survival in resected patients.
BACKGROUND:Hepatic ischemia-reperfusion injury (IRI) causes donor graft dysfunction and increases mortality after liver transplantation (LT). Bilobalide (BB), a natural sesquiterpene lactone extracted from Ginkgo biloba leaves, exhibits anti-inflammatory and anti-necrotic bioactivities. However, there is no study currently on the use of bilobalide in IRI therapy for liver transplant. This study aimed to investigate whether bilobalide protects grafted livers from IRI and to explore the underlying mechanisms. METHODS:Donor livers preserved in histidine-tryptophan-ketoglutarate (HTK) solution for 5 h underwent orthotopic liver transplantation in Sprague-Dawley rats. Following LT, rats were administered intraperitoneal injections of bilobalide (30 mg/kg, LT + BB group), saline (LT group), or N-acetylcysteine (150 mg/kg, LT + NAC group) at two-time points: immediately after surgery and again at 12 h post-transplant. Serum liver enzymes levels at 24 h after transplantation were measured. Liver tissues underwent hematoxylin and eosin (H&E) staining to confirm the injury. To examine hepatocyte apoptosis, both TUNEL staining and Western blot analysis were employed. Inflammatory responses in liver tissue were examined using immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Potential signaling pathways were identified through transcriptome sequencing (RNA-seq) and subsequently validated by Western blot analysis. In addition, macrophage polarization was evaluated using immunofluorescence and Western blot. RESULTS:The LT + BB group exhibited significantly milder liver injury and hepatocyte apoptosis compared to the LT group. The LT + NAC group also showed reduced liver injury and apoptosis, although the protective effects were less pronounced than those observed in the LT + BB group. Bilobalide treatment significantly reduced inflammatory cell infiltration and suppressed pro-inflammatory cytokine expression. RNA-seq and Western blot analyses demonstrated that bilobalide inhibited the activation of the nuclear factor Kappa B (NF-κB) signaling pathway in transplanted liver tissue. Immunofluorescence and Western blot results further revealed that bilobalide suppressed macrophage polarization toward the M1 phenotype. CONCLUSIONS:Bilobalide protects the transplanted liver from IRI by regulating macrophage polarization through NF-κB signaling pathway.
Per- and polyfluoroalkyl substances (PFASs), such as perfluorooctanoic acid and perfluorooctane sulfonic acid, are synthetic compounds that are persistent in the environment and are widely used in industrial and consumer products. Their bioaccumulative potential and pervasive human exposure have raised serious concerns about hepatotoxicity and carcinogenicity. This review thoroughly examines current epidemiological and experimental evidence linking PFASs exposure to an increased risk of liver cancer, particularly hepatocellular carcinoma. Epidemiological studies show higher PFASs levels in hepatocellular carcinoma patients, with notable sex-specific associations suggesting hormonal influences. Mechanistic studies indicate that PFASs disrupt lipid and bile acid metabolism, induce oxidative stress, cause epigenetic alterations, and activate key oncogenic pathways including peroxisome proliferator-activated receptor α, PI3K/AKT/mTOR, and necroptosis inhibition. Together, these effects collectively foster pro-tumorigenic microenvironment that promotes malignant transformation and proliferation. Despite growing evidence, significant knowledge gaps remain regarding PFASs effects on liver cancer, tumor immunity, and outcomes from mixed exposure. Future research should prioritize large-scale longitudinal studies, in-depth mechanistic investigations, and the development of targeted therapeutic and regulatory strategies to reduce PFASs-associated liver cancer risks.
