Hepatocellular carcinoma (HCC) stands as the fifth most prevalent malignant tumor on a global scale and presents as the second leading cause of cancer-related mortality. DNA damage-based radiotherapy (RT) plays a pivotal role in the treatment of HCC. Nevertheless, radioresistance remains a primary factor contributing to the failure of radiation therapy in HCC patients. In this study, we investigated the functional role of transketolase (TKT) in the repair of DNA double-strand breaks (DSBs) in HCC. Our research unveiled that TKT is involved in DSB repair, and its depletion significantly reduces both non-homologous end joining (NHEJ) and homologous recombination (HR)-mediated DSB repair. Mechanistically, TKT interacts with PARP1 in a DNA damage-dependent manner. Furthermore, TKT undergoes PARylation by PARP1, resulting in the inhibition of its enzymatic activity, and TKT can enhance the auto-PARylation of PARP1 in response to DSBs in HCC. The depletion of TKT effectively mitigates the radioresistance of HCC, both in vitro and in mouse xenograft models. Moreover, high TKT expression confers resistance of RT in clinical HCC patients, establishing TKT as a marker for assessing the response of HCC patients who received cancer RT. In summary, our findings reveal a novel mechanism by which TKT contributes to the radioresistance of HCC. Overall, we identify the TKT-PARP1 axis as a promising potential therapeutic target for improving RT outcomes in HCC.

The structural components of the thymus are essential for guiding T cell development, but a thorough spatial view is still absent. Here we develop the TSO-his tool, designed to integrate multimodal data from single-cell and spatial transcriptomics to decipher the intricate structure of human thymus. Specifically, we characterize dynamic changes in cell types and critical markers, identifying ELOVL4 as a mediator of CD4⁺ T cell positive selection in the cortex. Utilizing the mapping function of TSO-his, we reconstruct thymic spatial architecture at single-cell resolution and recapitulates classical cell types and their essential co-localization for T cell development; additionally, previously unknown co-localization relationships such as that of CD8αα with memory B cells and monocytes are identified. Incorporating VDJ sequencing data, we also delineate distinct intermediate thymocyte states during αβ T cell development. Overall, these insights enhance our understanding of thymic biology and may inform therapeutic interventions targeting T cell-mediated immune responses.

Targeting base excision repair (BER) has been an attractive strategy in cancer therapeutics. RNA‐binding motif protein 39 (RBM39) modulates the alternative splicing of numerous genes involved in cancer occurrence and progression. However, whether and how RBM39 regulates BER in hepatocellular carcinoma (HCC) remain unclear. Here, we found that under oxidative stress, RBM39 degradation or knockdown decreased BER efficiency in HCC cells using a well‐designed BER reporter. Further assays showed that RBM39 promoted HCC cell proliferation, migration, and invasion, enhancing cell survival and inhibiting apoptosis. Mechanistically, RBM39 interacted with the mRNA of the essential glycosidase 8‐oxoguanine‐DNA glycosylase 1 (OGG1), thereby stabilising OGG1 mRNA. This in turn increases OGG1 expression and promotes BER efficiency in HCC. Moreover, data suggested that RBM39 degradation, combined with oxidative damage, could be more effective for HCC treatment than monotherapy, both in vitro and in xenograft mice models. Overall, we demonstrated that RBM39 regulated OGG1 stabilisation and improved BER efficiency, suggesting that combining the RBM39 degradant indisulam with the oxidising agent KBrO₃ could be an emerging strategy for HCC treatment.

Chemoresistance remains the primary barrier to improving clinical outcomes in gastric cancer (GC) patients. Here, we identify dipeptidyl peptidase 3 (DPP3) as a pivotal regulator of chemosensitivity in GC. We demonstrate that elevated DPP3 expression correlates with a favorable clinical prognosis and enhances the response of GC cells to chemotherapy. Mechanistically, DPP3 interacts with SLC3A2 and promotes its degradation at both mRNA and protein levels, thereby impairing the function of the cystine/glutamate antiporter. This destabilization restricts cystine uptake, depletes glutathione synthesis, and potently trigers ferroptosis. Furthermore, DPP3 deficiency promotes SLC3A2 stability and activates antioxidant response, which subsequently mitigates chemotherapy-induced DNA damage and facilitates cell survival. In functional studies, DPP3 overexpression sensitizes GC cells to platinum-based chemotherapies by triggering oxidative stress and ferroptosis, whereas DPP3 depletion impairs therapeutic efficacy in both cell line-derived xenograft and patient-derived organoid models. Collectively, these findings establish the DPP3-SLC3A2 axis as a critical regulatory node in GC metabolic adaptation and chemoresistance, positioning DPP3 as a promising therapeutic target to enhance the efficacy of conventional chemotherapy in GC