Emerging evidence indicates that transfer RNA (tRNA)‐derived small RNAs (tsRNAs), originated from tRNA with high abundance RNA modifications, play an important role in many complex physiological and pathological processes. However, the biological functions and regulatory mechanisms of modified tsRNAs in cancer remain poorly understood. Here, it is screened for and confirmed the presence of a novel m⁷G‐modified tsRNA, m⁷G‐3′‐tiRNA Lys^TTT (mtiRL), in a variety of chemical carcinogenesis models by combining small RNA sequencing with an m⁷G small RNA‐modified chip. Moreover, it is found that mtiRL, catalyzed by the tRNA m⁷G‐modifying enzyme mettl1, promotes bladder cancer (BC) malignancy in vitro and in vivo. Mechanistically, mtiRL is found to specifically bind the oncoprotein Annexin A2 (ANXA2) to promote its Tyr24 phosphorylation by enhancing the interactions between ANXA2 and Yes proto‐oncogene 1 (Yes1), leading to ANXA2 activation and increased p‐ANXA2‐Y24 nuclear localization in BC cells. Together, these findings define a critical role for mtiRL and suggest that targeting this novel m⁷G‐modified tsRNA can be an efficient way for to treat BC.

Hyperoxaluria, including primary and secondary hyperoxaluria, is a disorder characterized by increased urinary oxalate excretion and could lead to recurrent calcium oxalate kidney stones, nephrocalcinosis and eventually end stage renal disease. For secondary hyperoxaluria, high dietary oxalate (HDOx) or its precursors intake is a key reason. Recently, accumulated studies highlight the important role of gut microbiota in the regulation of oxalate homeostasis. However, the underlying mechanisms involving gut microbiota and metabolite disruptions in secondary hyperoxaluria remain poorly understood. Here, we investigated the therapeutic efficacy of fecal microbiota transplantation (FMT) sourced from healthy rats fed with standard pellet diet against urinary oxalate excretion, renal damage and calcium oxalate (CaOx) crystal depositions via using hyperoxaluria rat models. We observed dose-dependent increases in urinary oxalate excretion and CaOx crystal depositions due to hyperoxaluria, accompanied by significant reductions in gut microbiota diversity characterized by shifts in Ruminococcaceae_UCG-014 and Parasutterella composition. Metabolomic analysis validated these findings, revealing substantial decreases in key metabolites associated with these microbial groups. Transplanting microbes from healthy rats effectively reduced HDOx-induced urinary oxalate excretion and CaOx crystal depositions meanwhile restoring Ruminococcaceae_UCG-014 and Parasutterella populations and their associated metabolites. Furthermore, FMT treatment could significantly decrease the urinary oxalate excretion and CaOx crystal depositions in rat kidneys via, at least in part, upregulating the expressions of intestinal barrier proteins and oxalate transporters in the intestine. In conclusion, our study emphasizes the effectiveness of FMT in countering HDOx-induced hyperoxaluria by restoring gut microbiota and related metabolites. These findings provide insights on the complex connection between secondary hyperoxaluria caused by high dietary oxalate and disruptions in gut microbiota, offering promising avenues for targeted therapeutic strategies.

It is urgent to develop an alternative dynamic therapy-based method to overcome the limited efficacy of traditional therapy methods for bladder cancer and the damage caused to patients. Sonodynamic therapy (SDT) has the advantages of high tissue penetration, high spatiotemporal selectivity, and being non-invasive, representing an emerging method for eradicating deep solid tumors. However, the effectiveness of SDT is often hindered by the inefficient production of reactive oxygen species and the nondegradability of the sonosensitizer. To improve the anti-tumor effect of SDT on bladder cancer, herein, a BP-based heterojunction sonosensitizer (BFeSe ₂ ) was synthesized by anchoring FeSe ₂ onto BP via P–Se bonding to enhance the stability and the effect of SDT. As a result, BFeSe ₂ showed great cytotoxicity to bladder cancer cells under ultrasound (US) irradiation. BFeSe ₂ led to a notable inhibition effect on tumor growth in subcutaneous tumor models and orthotopic tumor models under US irradiation. In addition, BFeSe ₂ could also enhance T2-weighted magnetic resonance imaging (MRI) to achieve monitoring and guide treatment of bladder cancer. In general, BFeSe ₂ sonosensitizer integrates MRI functions for precise treatment, promising great clinical potential for the theranostics of bladder cancer.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are recognized as critical environmental health hazards, however, their toxicity mechanisms in specific organ systems remain poorly characterized. This study systematically investigated the chain length-dependent nephrotoxicity of PFAS and their inhibitory effects on renal carboxylesterase (CES) activity. In vitro experiments revealed that PFAS were cytotoxic to Human Kidney-2 (HK-2) cells in a dose-dependent and chain length-dependent manner. Furthermore, functional group modification significantly affected the toxicity, perfluoroalkyl carboxylic acids (PFCA) showed the strongest toxic effects compared to fluorotelomer alcohols (FTOH) and perfluoroiodides of the same carbon chain length. PFAS inhibited CES activity in a concentration-dependent manner, with stronger inhibitory effects observed at higher concentrations. PFCA showed the strongest inhibition of CES activity and chain length-dependent manner. Molecular simulations indicated that the PFAS easily bind to CES, suggesting PFAS may affect the activity by affecting secondary structure of CES. In vivo experiments revealed that exposure to perfluorocapric acid (PFDA) in C57BL/6 mice significantly suppressed renal CES activity and induced kidney injury, whereas perfluorohexanoic acid (PFHxA) exerted negligible effects. In addition, kidney weight was positively correlated with CES activity, suggesting a potential causal relationship between CES and PFAS-induced nephrotoxicity. Overall, this study not only provides new insights into the toxicological mechanisms of PFAS-laying a scientific foundation for the safety assessment of alternative compounds and the formulation of risk management strategies-but also validates the reliability of in vitro cell-based assays for the early screening of PFAS biotoxicity.

Gut microbial dysbiosis and the resultant metabolic disorder are intimately associated with calcium oxalate (CaOx) stone formation. Renal CaOx crystal deposition is one of the primary initiating factors of CaOx formation; however, the critical signaling metabolites communicating along the gut-kidney axis, and their regulation on renal CaOx crystal deposition remain unclear. Here, we investigate the role of gut microbiota-associated unconjugated bilirubin (UCB) metabolism in renal CaOx crystalline pathogenesis. The UCB was first distinguished as a significant risk factor of renal CaOx crystal deposition, by transplantation of fecal microbiota derived from healthy rat (healthy-FMT) to alleviate the renal CaOx crystal deposition in rat models, which was also testified in CaOx stone patients. Further experiments showed that UCB could increase renal CaOx crystal deposition significantly in both rat and Drosophila models. Mechanistically, UCB can promote apoptosis in renal tubular epithelial cells, enhance oxalate secretion by upregulating Slc26a6 expression, and facilitate CaOx crystal nucleation and aggregation, all of which contribute to renal CaOx crystalline pathogenesis. Furthermore, we identified significant gut microbiota dysbiosis in renal CaOx crystal deposition rats, particularly in β-glucuronidase (β-GD) and bilirubin reductase (BilR)-related dysbiosis, which modulate UCB levels and its enterohepatic circulation. These findings suggest that UCB is a novel regulator of renal CaOx crystal deposition, and targeting its metabolism via modulation of the gut microbiota may offer a promising therapeutic strategy for preventing renal CaOx crystal deposition-related nephropathy.