Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive malignant tumors globally, with a notably low five-year survival rate. Its high mortality is largely attributed to challenges in early detection. Extracellular vesicles (EVs) are naturally occurring nanoparticles secreted by nearly all cell types and carry a diverse array of bioactive molecules, including proteins, nucleic acids (particularly non-coding RNAs), and lipids. EVs play pivotal roles in remodeling the tumor microenvironment and driving cancer progression through intercellular communication. Accumulating evidence has established that EVs are critically involved in the pathogenesis of HCC and are emerging as promising biomarkers for its early detection. With advances in EV isolation technologies, these vesicles have garnered considerable attention in the field of liquid biopsy for HCC. This review provides a comprehensive overview of the diagnostic potential of EV-derived biomarkers in HCC, including DNA, RNA, proteins, and lipids. Additionally, it discusses the advantages of integrating multi-omics approaches for HCC diagnosis. Furthermore, the review highlights the technical challenges in EV isolation and characterization, as well as the crucial role of reference genes in the standardization of EV data. These insights underscore the potential of EVs as novel, minimally invasive liquid biopsy biomarkers for the early diagnosis of HCC.

Liver fibrosis is characterized by the excessive deposition of extracellular matrix, a process primarily driven by activated hepatic stellate cells (HSCs), and currently lacks effective therapy. Cathepsin K (CTSK) exhibits context-dependent roles across organ systems in fibrosis, but its function in liver fibrosis is unclear. This study aimed to investigate the role and underlying mechanisms of CTSK during liver fibrosis.

CTSK expression was analyzed in human fibrotic liver samples via transcriptomic analysis and confirmed in murine fibrosis models. The function of CTSK was investigated in both primary HSCs and LX-2 cells by assessing its effects on cell activation, proliferation, apoptosis, and the underlying signaling pathways following CTSK overexpression. The therapeutic potential was evaluated using an adeno-associated virus serotype 8 to overexpress CTSK in two etiologically distinct murine fibrosis models.

CTSK was upregulated in activated HSCs and fibrotic livers. Furthermore, we discovered that it mediates a negative feedback loop to inhibit the TGF-β/Smad pathway via Smad7/Smurf2-dependent TGF-β receptor-I degradation, thereby suppressing HSC activation and proliferation. CTSK also induced mitochondrial apoptosis through Bax/Bcl-2 imbalance and caspase-3 activation. Together, these actions contribute to the anti-fibrotic effect of CTSK. Notably, adeno-associated virus serotype 8-mediated CTSK overexpression attenuated liver fibrosis across multiple murine models.

Our study demonstrates that elevated CTSK functions as an endogenous protective factor that attenuates liver fibrosis. CTSK mediates negative feedback inhibition of the TGF-β pathway while concurrently promoting the mitochondrial apoptosis pathway. The dual anti-fibrotic mechanisms identify CTSK as a promising therapeutic target for liver fibrosis.

Accumulating evidence indicates that fecal syndecan-2 (SDC2) methylation is a promising biomarker for early detection of colorectal cancer. This study aimed to investigate the diagnostic efficacy of fecal SDC2 methylation testing for adenomas and evaluate the risk stratification efficacy of the Asia-Pacific Colorectal Screening Scoring (APCS) combined with SDC2 methylation status.

This was a prospective, multicenter diagnostic study. Adult participants with no history of colonoscopy within the past three years were enrolled. Demographic data were collected, and APCS scores were evaluated. All participants underwent fecal SDC2 methylation testing and colonoscopy. Colonoscopy outcomes and pathological results of any polyps served as reference standards. The fecal SDC2 methylation test and reference standard assessments were conducted in a blinded manner. The APCS-SDC2 scoring system was developed by integrating fecal SDC2 methylation results with APCS scores, and its efficacy was assessed.

In total, 985 participants were enrolled, among whom 62 (6.3%) tested positive for fecal SDC2 methylation. The sensitivity and specificity of fecal SDC2 methylation in detecting advanced adenomas were 31.3% (95% confidence interval (CI): 21.6–42.7%) and 96.1% (95% CI: 94.6–97.2%), respectively. The APCS-SDC2 scoring system yielded an area under the curve of 0.7032 (95% CI: 0.5869–0.8195) for advanced adenomas in the validation set. For advanced adenoma screening, the specificity of the APCS-SDC2 score was higher than that of the APCS score (96.3% vs. 66.7%; P < 0.001).

A positive fecal SDC2 methylation test indicated a higher risk of advanced adenoma, and colonoscopy should be prioritized. The APCS-SDC2 scoring system may improve risk stratification performance, particularly by increasing specificity.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for effective therapies. Although miR-125b-5p shows therapeutic potential, its efficacy in metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC and the underlying mechanisms remain unclear. In this study, we aimed to develop a magnetic resonance imaging (MRI)-trackable miR-125b-5p-engineered MSC platform for HCC therapy and to determine whether MASLD attenuates its antitumor efficacy through metabolic reprogramming.

Bone marrow mesenchymal stem cells (MSCs) were genetically engineered to coexpress miR-125b-5p (a therapeutic gene) and ferritin heavy chain (Fth; a MRI reporter gene), enabling sustained delivery and real-time tracking. Orthotopic HCC models with or without MASLD were established to evaluate therapeutic outcomes. In vivo MRI, histological analyses, and bioinformatics approaches were used to assess efficacy and mechanisms.

Transplantation of miR-125b-5p-Fth-MSCs significantly suppressed HCC growth in vivo over an extended period. However, MASLD attenuated this therapeutic effect. Mechanistically, miR-125b-5p directly targeted hexokinase 2 (HK2), inhibiting HCC proliferation and migration through suppression of the PI3K/AKT/mTOR pathway. Fatty acid-induced lipotoxicity upregulated HK2 expression and counteracted the antitumor effects of miR-125b-5p.

Multigene-modified MSCs enable effective, MRI-monitored HCC therapy. MASLD diminishes the efficacy of miR-125b-5p through HK2 upregulation. These findings establish a multimodal theranostic framework for HCC and provide mechanistic insights into MASLD-associated therapeutic resistance.

Chaperone-like proteins are involved in the pathogenesis of coronavirus infection through regulation of the viral life cycle, immune response, and antigen presentation. A recently discovered class of chaperones, called heat-resistant obscure proteins (Hero proteins), performs functions similar to other molecular chaperones. This study aimed to investigate the association between the gene encoding the Hero protein SERF2 (Hero7) and the risk of severe COVID-19.

This case-control study was conducted according to the STROBE protocol. A total of 1,373 unrelated Russians (178 patients with severe COVID-19 and 1,195 controls) were recruited. Genotyping of rs4644832 in the SERF2 gene was performed using a probe-based polymerase chain reaction approach. The effects of the single nucleotide polymorphisms (SNPs) were analyzed using bioinformatics tools, including GTExPortal, eQTLGen, HaploReg, atSNP, Gene Ontology, Lung Disease and Common Metabolic Diseases Knowledge Portals, and the STRING database.

SNP rs4644832 in the SERF2 gene (effect allele G) was associated with a decreased risk of severe COVID-19 in the total sample (odds ratio (OR) = 0.56, 95% confidence interval (CI) 0.39–0.81, P = 0.001), females (OR = 0.51, 95% CI 0.31–0.87, P = 0.006), non-smokers (OR = 0.46, 95% CI 0.29–0.74, P = 0.0004), individuals with body mass index ≥ 25 (OR = 0.42, 95% CI 0.25–0.7, P = 0.0004), individuals with low fruit and vegetable intake (OR = 0.38, 95% CI 0.22–0.67, P = 0.0004), and individuals with low physical activity (OR = 0.41, 95% CI 0.23–0.75, P = 0.002).

The G allele of rs4644832 in the SERF2 gene appears to have a protective effect against severe COVID-19. Functional annotation of rs4644832 suggests that it may influence COVID-19 pathogenesis through regulation of proteostasis, ubiquitination, inflammation-induced protein aggregation, the viral life cycle, and cytoskeletal functions.

Luteolin is a dietary flavonoid widely distributed in fruits and vegetables. It has attracted substantial preclinical interest due to its pleiotropic hepatoprotective effects against hepatic steatosis, inflammation, fibrosis, and hepatocellular carcinoma. By reviewing data from in vitro and in vivo studies, this review comprehensively synthesizes the full spectrum of liver-directed pharmacology of luteolin, covering metabolic and toxic liver injury, fibrosis, cancer, and viral hepatitis, while critically mapping each mechanism to specific disease contexts and systematically identifying the key challenges limiting its clinical translation. The underlying mechanisms of luteolin action involve activation of Nrf2-mediated antioxidant defense, suppression of NF-κB- and NLRP3-driven inflammatory responses, inhibition of hepatic stellate cell activation via the TGF-β/Smad and STAT3 pathways, and regulation of metabolic homeostasis through liver X receptor (LXR)/SREBP-1c and AMPK signaling. Despite well-characterized mechanisms in preclinical models, several critical gaps hinder its clinical translation: (1) Rigorous randomized controlled trials in well-defined patient populations are scarce, with only one combination supplement study reported. (2) The relative contribution of luteolin metabolites to its overall bioactivity remains poorly understood, even though derivatives such as luteolin-7-diglucuronide exhibit distinct pharmacological properties. Cell-type-specific delivery systems, which show promise in preclinical fibrosis and cancer models, have not been evaluated clinically. (3) Systematic studies on the synergistic effects of luteolin with standard-of-care drugs remain largely exploratory. Overall, luteolin is a promising multi-target nutraceutical for liver diseases, and its clinical translation requires optimized delivery strategies, investigation of metabolite activity, and well-designed human clinical trials.

Hepatic myelopathy, a rare neurological complication of decompensated chronic liver disease, profoundly impairs quality of life. While liver transplantation represents the only curative treatment for hepatic myelopathy, we report a case in which progressive and severe spastic paraparesis was markedly improved following embolization of a paraspinal vein shunt.

End-stage liver disease (ESLD) is characterized by a dramatic deterioration of liver function, frequently accompanied by systemic inflammatory storms and multiple organ failures. Central to the onset and progression of ESLD, systemic inflammation arises from complex interactions among various inflammatory signaling molecules and immune cells within and beyond the liver. As key inflammatory modulatory molecules, bioactive oxylipins have been increasingly recognized for their complex molecular mechanisms implicated in various diseases. This review aims to summarize recent findings regarding the molecular and immunological mechanisms through which oxylipins contribute to the development of liver injury and failure, with emphasis on both substantial intrahepatic and extrahepatic immune and inflammatory dysregulation associated with ESLD. Furthermore, this review discusses the translational potential of targeting oxylipins for clinical diagnosis, prognosis, and therapeutic intervention in ESLD.