Xuan Xia

Adenine base editors (ABEs), which achieve A·T to G·C conversions in the genome precisely, symbolize a groundbreaking development in genetic engineering across animal, plant, and microbial systems. This review systematically summed up the research progress and current challenges of ABE in medical and biological applications: it outlined the historical context and pivotal milestones of its technological development; it emphasized major therapeutic advances for genetic diseases including spinal muscular atrophy, mitochondrial genetic disorders, and hyperlipidemia; it provided a comprehensive overview of its prospective uses for enhancing genetic traits in agricultural crops, including grains and fruits; this review conducted a multidimensional assessment of ABE performance through systematic comparison with other base editing technologies, comprehensively evaluating both editing efficiency and inherent limitations. It specifically addresses biosecurity risks such as off-target effects and genomic instability. Finally, safety concerns were proposed as the central challenge hindering its clinical translation, although ABE holds immense promise for precision medicine and agricultural breeding. Unlike previous reviews that mainly summarized early ABE development and general applications, this review particularly emphasizes recently engineered ABE systems, translational bottlenecks, delivery strategies, comparative clinical feasibility, and unresolved biosafety challenges that currently limit broader therapeutic and agricultural applications.

Rifampicin (RFP) is a well-known first-line antitubercular drug recommended by the World Health Organization. However, RFP-induced hepatotoxicity makes it impractical for use in long-term antitubercular therapy, and its mechanism is still incompletely understood. This study decrypts the mechanism of aberrant cholesterol metabolism in RFP-mediated liver injury and explores the protective effects of genistein (GEN), an isoflavone isolated from the dyer's broom plant (Genista tinctoria), when used in conjunction with RFP. RFP significantly promoted the formation of lipid droplets, increasing cholesterol deposition in liver by reducing cholesterol 25-hydroxylase (CH25H) and its downstream effector LXRα-ABCA to decrease cholesterol efflux. GEN upregulated CH25H and ultimately relieved RFP-induced liver injury; furthermore, replacing endogenous 25-hydroxycholesterol (25HC) both in vivo and in vitro accordingly rescued the hepatotoxicity induced by RFP. Finally, molecular docking and cellular thermal shift assay (CETSA) showed that RFP could bind to CH25H and impair its stability, an interaction that could be reversed by GEN. Thus, RFP restrains cholesterol efflux by reducing the CH25H-LXRα-ABCA axis to trigger steatosis, while GEN restores this pathway by upregulating CH25H, facilitating cholesterol efflux and mitigating RFP-induced liver injury.

Hepatotoxicity is a significant clinical challenge that severely limits the therapeutic application of isoniazid (INH), a globally recommended first‐line anti‐tuberculosis (TB) drug. Despite its essential role in TB treatment, the underlying mechanisms of INH‐induced liver injury remain incompletely understood. This study investigates the role of Ten‐eleven translocation 2 (Tet2) in INH‐induced hepatotoxicity and elucidates its regulatory mechanism on autophagy during hepatocellular injury. The results showed that INH administration significantly enhanced hepatocyte autophagy, as evidenced by elevated LC3II and decreased P62 levels. Tet2 expression exhibited dose‐ and time‐dependent reduction manner following INH exposure. In vitro, Tet2 silencing exacerbated INH‐induced autophagy and hepatotoxicity. Consistently, Tet2 conventional knockout (Tet2KO) mice exhibited more severe liver injury compared to their matched wild‐type siblings under INH administration, accompanied by significantly increased hepatic LC3II and decreased P62 expression. Notably, vitamin C, a known cofactor that enhances Tet‐mediated DNA demethylation, not only restored Tet2 expression and function but also attenuated INH‐triggered autophagy and concomitantly alleviated liver injury in INH‐treated mice. In conclusion, our findings establish Tet2 as a crucial protective factor against INH‐induced liver injury by modulating autophagy. Enhancement of Tet2 expression, particularly through vitamin C supplementation, presents a promising strategy for mitigating hepatotoxicity in TB patients receiving INH therapy.

Background: Numerous investigations have underscored the causal effect between chronic pain (CP) and gut microbiota, jointly contributing to the onset and development of widespread CP. Nonetheless, there was still uncertainty about the causal effect between gut microbiota and chronic regional pain (CRP).Methods: Genome-wide association study (GWAS) summary data of gut microbial taxa (MiBioGen Consortium: 211 microbiotas and the Dutch Microbiome Project: 207 microbiotas) and eight types of CRP were used to reveal the causal effect between persistent pain in a specific region of the body and gut microbiota. A two-sample bidirectional Mendelian randomization (MR) design was used. In order to ensure the accuracy of the results, multiple sensitivity analyses were employed.Results: This study uncovered significant causal associations between six gut microbial taxa and three types of CRP (forward: Genus Parabacteroides for general pain; Class Bacteroidia, Order Bacteroidales, and Phylum Bacteroidetes for back pain. Reverse: knee pain for Genus Howardella and Order Coriobacteriales) by forward and reverse MR analysis. These findings had been verified by a rigorous Bonferroni correction. Furthermore, this research identified 19 microbial taxa that exhibited potential correlations with four types of CRP. There are no significant or potential gut microbiotas that were associated with other types of CRP, including fascial pain, stomach or abdominal pain, and hip pain.Conclusion: This two-sample bidirectional MR analysis unveiled the causality between gut microbial taxa and eight CRP conditions. The findings reveal the interplay between CRP and 6 gut microbiotas while also delineating 19 potential specific microbial taxa corresponding to diverse locations of persistent pain.

Drug-induced liver injury (DILI) is characterized by hepatocyte injury, cholestasis injury, and mixed injury. The liver transplantation is required for serious clinical outcomes such as acute liver failure. Current studies have found that many mechanisms were involved in DILI, such as mitochondrial oxidative stress, apoptosis, necroptosis, autophagy, ferroptosis, etc. Ferroptosis occurs when hepatocytes die from iron-dependent lipid peroxidation and plays a key role in DILI. After entry into the liver, where some drugs or chemicals are metabolized, they convert into hepatotoxic substances, consume reduced glutathione (GSH), and decrease the reductive capacity of GSH-dependent GPX4, leading to redox imbalance in hepatocytes and increase of reactive oxygen species (ROS) and lipid peroxidation level, leading to the undermining of hepatocytes; some drugs facilitated the autophagy of ferritin, orchestrating the increased ion level and ferroptosis. The purpose of this review is to summarize the role of ferroptosis in chemical- or drug-induced liver injury (chemical/DILI) and how natural products inhibit ferroptosis to prevent chemical/DILI.

Background and aim: Previous studies have reported an association between gut microbiota and cirrhosis. However, the causality between intestinal flora and liver cirrhosis still remains unclear. In this study, bi-directional Mendelian randomization (MR) analysis was used to ascertain the potential causal effect between gut microbes and cirrhosis.Methods: Large-scale Genome Wide Association Study (GWAS) data of cirrhosis and gut microbes were obtained from FinnGen, Mibiogen consortium, and a GWAS meta-analysis of Alcoholic cirrhosis (ALC). Two-sample MR was performed to determine the causal relationship between gut microbiota and cirrhosis. Furthermore, a bi-directional MR analysis was employed to examine the direction of the causal relations.Result: In MR analysis, we found that 21 gut microbiotas were potentially associated with cirrhosis. In reverse MR analysis, 11 gut microbiotas displayed potentially associations between genetic liability in the gut microbiome and cirrhosis. We found that the family Lachnospiraceae (OR: 1.59, 95% CI:1.10–2.29) might be harmful in cirrhotic conditions (ICD-10: K74). Furthermore, the genus Erysipelatoclostridium might be a protective factor for cirrhosis (OR:0.55, 95% CI:0.34–0.88) and PBC (OR:0.68, 95% CI:0.52–0.89). Combining the results from the MR analysis and reverse MR analysis, we firstly identified the Genus Butyricicoccus had a bi-directional causal effect on PBC (Forward: OR: 0.37, 95% CI:0.15–0.93; Reverse: OR: 1.03, 95% CI:1.00–1.05).Conclusion: We found a new potential causal effect between cirrhosis and intestinal flora and provided new insights into the role of gut microbiota in the pathological progression of liver cirrhosis.

Neutrophil extracellular traps (NETs) are known as extracellular fibers networks consisting of antimicrobial proteins and decondensated chromatin DNA released by activated neutrophils. NETosis is a NETs-induced neutrophilic cell death which is unique from necrosis or apoptosis. Besides its neutralizing pathogen, NETosis plays a crucial role in diabetes and diabetes-related complications. In patients with diabetes, NETs-releasing products are significantly elevated in blood, and these findings confirm the association of NETosis and diabetic complications, including diabetic wound healing, diabetic retinopathy, and atherosclerosis. This article briefly summarizes the mechanisms of NETosis and discusses its contribution to the pathogenesis of diabetes-related complications and suggests new therapeutic targets by some small molecule compounds.

IKKε (inhibitor of nuclear factor kappa-B kinase ε) is a member of the noncanonical NF-κB pathway. It participates in the inflammatory response and innate immunity against bacteria. In recent decades, IKKε has been closely associated with metabolic regulation. Inhibition of the IKKε pathway can improve fat deposition in the liver, reduce subcutaneous fat inflammation, and improve liver gluconeogenesis in obesity. IKKε is expected to be a new therapeutic target for metabolic diseases such as nonalcoholic fatty liver disease, diabetes, and obesity. Herein, we summarize the structural characterization, physiological function, and pathological role of IKKε in metabolic diseases and small molecule inhibitors of IKKε.