Xi Zeng

UDP-glucuronosyltransferases (UGTs) are a key family of phase II metabolic enzymes in humans that play a central role in maintenance of metabolic homeostasis and drug disposition by catalyzing glucuronidation of endogenous and exogenous substances. UGT-mediated metabolism of antitumor drugs plays a dual role in tumor drug resistance, emerging as a hotspot in cancer therapy. This review outlines the structural characteristics, classification system, tissue distribution, and multilevel regulation of UGTs, with a focus on their bidirectional roles in tumor drug resistance, i.e., promotion of resistance through metabolic clearance and inhibition of resistance through metabolic activation. This review also discusses strategies of multidimensional tumor resistance intervention based on UGTs, and we also discussed the challenges in the clinical translation of current UGT-targeting strategies. To date, most data on UGTs were derived from in vitro and preclinical models; clinical validation remains limited, and the dual roles of UGTs are highly context-dependent. This review article provides a perspective for comprehensive understanding of UGT-mediated tumor resistance and offers theoretical foundations and practical directions for development of novel antitumor strategies.

Objective: Aldo‐keto reductase 1B10 (AKR1B10) is overexpressed in hepatocellular carcinoma (HCC). This study aimed to evaluate its diagnostic efficacy for early and alpha‐fetoprotein (AFP)‐negative HCC, and its potential role in assessing radical resection and early recurrence. Methods: A large‐scale multicentre clinical study enrolled 1 352 subjects from three medical centres, including HCC, benign liver diseases, and non‐hepatocyte cancers. Serum samples were collected for AKR1B10 and AFP testing, and clinical and imaging data were collected for analysis. Results: Serum AKR1B10 markedly increased in HCC patients to 1419.51 ± 89.09 pg/mL, compared to 177.96 ± 9.78 pg/mL in healthy controls. Receiver operating characteristic (ROC) curve analysis showed that for HCC diagnosis, AKR1B10 had an Area under the curve (AUC) of 0.866, sensitivity of 73.10%, and specificity of 95.24%, compared to AFP with 0.750, 64.27%, and 82.14%, respectively. In early HCC, AKR1B10 yielded an AUC of 0.800, a sensitivity of 65.8%, and a specificity of 91.67%, better than AFP (0.717, 59.83%, and 88.1%, respectively). AKR1B10 was positive in 69.27% of AFP‐negative HCC cases and showed an AUC of 0.852, a sensitivity of 72.2%, and a specificity of 90.48%. In patients with HCC undergoing curative resection, serum AKR1B10 levels declined to normal within 3–5 days. At 1–3 months after surgery, serum AKR1B10 had a concordance of 94.41% with imaging data, compared to 70.63% for AFP. Conclusion: AKR1B10 is a useful serum marker for the diagnosis of early and AFP‐negative HCC and shows potential in assessing curative resection and early recurrence.

Circadian Locomotor Output Cycles Kaput (CLOCK) is a core circadian gene encoding a transcription factor essential for maintaining physiological rhythms, and has more recently been implicated in cancer biology. In this study, we uncover an unrecognized tumor-suppressive role of CLOCK in nasopharyngeal carcinoma (NPC). Mechanistically, CLOCK directly activates NBR1 transcription, leading to the stabilization of p62/SQSTM1 and the co-assembly of NBR1-p62 condensates via liquid-liquid phase separation (LLPS). These condensates serve as scaffolds for the recruitment of the E3 ubiquitin ligase TRIM38, which mediates the ubiquitination and proteasomal degradation of TAK1-binding protein 2 (TAB2), thereby attenuating NF-κB signaling. Functionally, this axis suppresses NPC cell proliferation and migration. Our findings reveal a novel CLOCK–NBR1/p62–TRIM38–TAB2 pathway that links circadian gene to LLPS-driven tumor suppression in NPC, providing new insights into the role of circadian genes in cancer biology and pointing to a potential therapeutic target for this malignancy.

Cancer remains one of the most pressing global health challenges due to its high incidence and mortality. Intratumoral and intertumoral heterogeneity pose significant challenges to effective treatment, driving metastasis, recurrence, therapeutic resistance and ultimately treatment failure. The development of precision medicine urgently requires in vitro models that can faithfully capture patient‐specific tumour complexity to guide individualised therapies. Recent advances in stem cell‐based three‐dimensional culture technologies have facilitated the establishment of organoid systems that closely replicate the architecture, molecular features, genomic alterations and microenvironment of primary tumours. Compared with conventional cell lines, organoids exhibit superior fidelity, making them a transformative platform for cancer modelling. They hold considerable promise for high‐throughput drug screening, therapeutic response prediction, biomarker discovery and the design of personalised treatment strategies. Despite these advances, clinical translation is still hindered by challenges, such as the lack of standardisation, prolonged culture periods, high costs and regulatory and ethical constraints. This review summarises recent progress in tumour organoid research, with particular emphasis on their ability to replicate the genetic and biological features of parental tumours. We highlight their translational applications in immunotherapy, drug sensitivity prediction and individualised treatment, while also proposing strategies to address current limitations aiming to accelerate the integration of organoid technologies into precision oncology.

The development and progression of cardiovascular diseases (CVDs) are closely linked to an imbalance in endoplasmic reticulum homeostasis. UFMylation, a recently identified ubiquitin‐like post‐translational modification, plays a crucial role in maintaining cellular homeostasis by regulating substrate protein functions through a unique enzymatic cascade. Accumulating evidence has demonstrated that UFMylation exerts complex regulatory effects on the pathogenesis of atherosclerosis, primarily by modulating endothelial function, macrophage foam cell formation, and inflammasome activation. Furthermore, UFMylation of the calcium‐regulating protein SPCA1 disrupts calcium homeostasis in hypertrophic cardiomyopathy. Conversely, UFMylation also exhibits protective roles; for instance, it prevents pathological cardiac remodeling in heart failure by maintaining endoplasmic reticulum function via its E3 ligase, UFL1. Accordingly, this review systematically summarizes these multifaceted protective mechanisms of UFMylation in CVDs. We also explore potential therapeutic strategies targeting UFMylation, discussing its promise as a CVD biomarker and the opportunities and challenges in developing UFMylation agonists. In‐depth research in this field is expected to provide novel theoretical foundations and precise intervention targets for the prevention and treatment of CVDs.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with chronic hepatitis B and C viral infections being major risk factors. To date, the lack of effective methods for monitoring the progression from viral infection to cancer remains a clinical issue. Alpha-fetoprotein (AFP) is a serum marker used for the detection of HCC; however, AFP levels remain negative in 30–40% of HCC cases and 60–70% of early-stage HCC cases. Aldo-keto reductase 1B10 (AKR1B10) has been reported as a serum marker for HCC. In this study, we report two cases of hepatitis B-related HCC that were persistently AFP-negative but showed a marked increase in serum AKR1B10 levels. These cases illustrate the complementary role of serum AKR1B10 in the diagnosis of AFP-negative HCC, serving as a hypothesis-generating approach. A prospective large-scale study is warranted to define the clinical value of AKR1B10 in AFP-negative HCC.

Chemotherapy remains a prevalent treatment for a wide range of tumors; however, the majority of patients undergoing conventional chemotherapy experience varying levels of chemoresistance, ultimately leading to suboptimal outcomes. The present article provided an in‑depth review of chemotherapy resistance in tumors, emphasizing the underlying factors contributing to this resistance in tumor cells. It also explored recent advancements in the identification of key molecules and molecular mechanisms within the primary chemoresistant pathways.

Many human diseases, such as malignant tumors and neurological diseases, have a complex pathophysiological etiology, often accompanied by aberrant epigenetic changes including various histone modifications. Plant homologous domain finger protein 8 (PHF8), also known as lysine-specific demethylase 7B (KDM7B), is a critical histone lysine demethylase (KDM) playing an important role in epigenetic modification. Characterized by the zinc finger plant homology domain (PHD) and the Jumonji C (JmjC) domain, PHF8 preferentially binds to H3K4me3 and erases repressive methyl marks, including H3K9me1/2, H3K27me1, and H4K20me1. PHF8 is indispensable for developmental processes and the loss of PHF8 enzyme activity is linked to neurodevelopmental disorders. Moreover, increasing evidence shows that PHF8 is highly expressed in multiple tumors as an oncogenic factor. These findings indicate that studying the role of PHF8 will facilitate the development of novel therapeutic agents by the manipulation of PHF8 demethylation activity. Herein, we summarize the current knowledge of PHF8 about its structure and demethylation activity and its involvement in development and human diseases, with an emphasis on nervous system disorders and cancer. This review will update our understanding of PHF8 and promote the clinical transformation of its predictive and therapeutic value.