Background: Lenvatinib resistance (LR) represents a significant obstacle in hepatocellular carcinoma (HCC) treatment. Aldo‐keto reductase family 1 member B10 (AKR1B10) is involved in tumour metabolic reprogramming; however, its role in LR remains unclear. Methods: Bioinformatics analyses of public databases were integrated and validated in established LR HCC cell lines. Functional assays (CCK‐8, flow cytometry and Seahorse XF analysis) were performed to assess proliferation, apoptosis and aerobic glycolysis. Post‐translational modifications of AKR1B10 were characterized using co‐immunoprecipitation, mass spectrometry and western blot. Results: AKR1B10 was identified as a critical driver of resistance by establishing a metabolic positive feedback loop. Bioinformatics analyses and experimental validation demonstrated that AKR1B10 upregulation correlates with therapeutic resistance. Functional studies indicated that AKR1B10 promotes resistance by enhancing aerobic glycolysis. Mechanistically, alanyl‐tRNA synthetase 1 mediates lactylation modification at AKR1B10 lysine 173 (K173), stabilizing AKR1B10 by blocking ubiquitin (Ub)‐proteasomal degradation. Stabilized AKR1B10 interacts physically with lactate dehydrogenase A (LDHA), promoting LDHA phosphorylation at Y10 and accelerating glycolytic lactate production. The increased lactate subsequently induces histone H3K18 lactylation (H3K18la), which transcriptionally upregulates LDHA expression. Thus, a self‐reinforcing AKR1B10–lactate–LDHA amplification circuit is formed. Clinical analyses confirmed elevated AKR1B10 expression in LR HCC patient tissues. Importantly, targeting this axis with the AKR1B10 inhibitor epalrestat (EPA) synergized with lenvatinib, overcoming resistance in xenograft mouse models and patient‐derived xenograft models. Conclusions: These findings establish AKR1B10 as both a biomarker and a therapeutic target in HCC. They reveal a novel lactylation‐driven glycolytic adaptation mechanism and support the clinical translation of combined EPA–lenvatinib therapy. Key points: AKR1B10 confers lenvatinib resistance by enhancing aerobic glycolysis in HCC cells. AKR1B10 undergoes AARS1‐mediated lactylation at K173, stabilizing it by antagonizing ubiquitin‐proteasomal degradation. AKR1B10 promotes LDHA Y10 phosphorylation, boosting lactate production, which drives H3K18la‐mediated transcriptional upregulation of LDHA, creating a feed‐forward loop. Targeting AKR1B10 with epalrestat synergizes with lenvatinib to overcome resistance in preclinical models.

Background: Ex vivo liver resection combined with autotransplantation is an effective therapeutic strategy for unresectable end-stage hepatic alveolar echinococcosis (HAE). However, ex vivo liver resection combined with autotransplantation is a technically demanding and time-consuming procedure associated with significant morbidity and mortality. The authors aimed to present our novel remnant liver-first strategy of in vivo liver resection combined with autotransplantation (IRAT) technique for treating patients with end-stage HAE. Methods: This retrospective study included patients who underwent IRAT between January 2014 and December 2020 at two institutions. Patients with end-stage HAE were carefully assessed for IRAT by a multidisciplinary team. The safety, feasibility, and outcomes of this novel technique were analyzed. Results: IRAT was successfully performed in six patients, with no perioperative deaths. The median operative time was 537.5 min (range, 501.3–580.0), the median anhepatic time was 59.0 min (range, 54.0–65.5), and the median cold ischemia time was 165.0 min (range, 153.8–201.5). The median intraoperative blood loss was 700.0 ml (range, 475.0–950.0). In-hospital complications occurred in two patients. No Clavien–Dindo grade III or higher complications were observed. At a median follow-up of 18.6 months (range, 15.4–76.0) , all patients were alive. No recurrence of HAE was observed. Conclusion: The remnant liver-first strategy of IRAT is feasible and safe for selected patients with end-stage HAE. The widespread adoption of this novel technique requires further studies to standardize the operative procedure and identify patients who are most likely to benefit from it.

Posttranslational modification succinylation plays a pivotal role in tumorigenesis across malignancies, yet its mechanistic contributions to hepatocellular carcinoma (HCC) pathogenesis and therapeutic resistance remain poorly characterized. In this study, we systematically demonstrated that the splicing factor SRSF11 undergoes functional consequential succinylation in HCC progression. Mechanistically, lysine acetyltransferase 2 A (KAT2A) directly interacts with SRSF11 to catalyze its succinylation at lysine 419 (K419), thereby enhancing DNA damage repair capacity in both in vitro and in vivo HCC models. Structural and functional analyses revealed that K419 succinylation stabilizes SRSF11-spliceosome interactions, which promote the inclusion of exon 10 of RAD52 through enhanced pre-mRNAs binding. This exon-specific splicing event preserves the RAD51-binding domain essential for homologous recombination (HR) repair, ultimately facilitating RAD52-RAD51 dimer assembly and HR-mediated genomic stabilization. Clinically, elevated SRSF11 expression is correlated with increased HR activity, radioresistance, and reduced survival in HCC patients. Notably, genetic disruption of the KAT2A-SRSF11 axis sensitizes HCC cells to radiation-induced apoptosis. Our findings establish succinylation as a novel regulatory mechanism linking alternative splicing to DNA repair fidelity in HCC, while proposing therapeutic targeting of this pathway to overcome radioresistance in advanced HCC.

Hepatocellular carcinoma (HCC) remains a global health challenge with a low early diagnosis rate and high mortality. The Rab GTPase (RAB) family plays an essential role in the occurrence and progression of HCC. Nonetheless, a comprehensive and systematic investigation of the RAB family has yet to be performed in HCC. We comprehensively assessed the expression landscape and prognostic significance of the RAB family in HCC and systematically correlated these RAB family genes with tumor microenvironment (TME) characteristics. Then, three RAB subtypes with distinct TME characteristics were determined. Using a machine learning algorithm, we further established a RAB score to quantify TME features and immune responses of individual tumors. Moreover, to better evaluate patient prognosis, we established a RAB risk score as an independent prognostic factor for patients with HCC. The risk models were validated in independent HCC cohorts and distinct HCC subgroups, and their complementary advantages guided clinical practice. Furthermore, we further confirmed that the knockdown of RAB13, a pivotal gene in risk models, suppressed HCC cell proliferation and metastasis by inhibiting the PI3K/AKT signaling pathway, CDK1/CDK4 expression, and epithelial-mesenchymal transition. In addition, RAB13 inhibited the activation of JAK2/STAT3 signaling and the expression of IRF1/IRF4. More importantly, we confirmed that RAB13 knockdown enhanced GPX4-dependent ferroptosis vulnerability, highlighting RAB13 as a potential therapeutic target. Overall, this work revealed that the RAB family played an integral role in forming HCC heterogeneity and complexity. RAB family-based integrative analysis contributed to enhancing our understanding of the TME and guided more effective immunotherapy and prognostic evaluation.

The serine/arginine-rich splicing factors (SRSF)-mediated alternative splicing plays an essential role in the occurrence and progression of hepatocellular carcinoma (HCC). However, the SRSF-based signature that can predict the prognosis and therapy efficiency is yet to be investigated in HCC. Here, we comprehensively assessed the landscape and prognostic significance of the SRSF family genes in HCC. Then, we screened the SRSF family-related genes for signature construction and explored their biological characteristics. We further established an SRSF score consisting of 18 SRSF-associated genes and evaluated its correlation with prognosis and drug sensitivity in HCC. The predictive power of the SRSF score was validated in independent HCC cohorts and different HCC subgroups. Moreover, we further investigated that knockdown of SRSF11, a pivotal gene in the SRSF score, inhibited CDK1-dependent proliferation and enhanced the drug sensitivity of HCC cells. Overall, our study identified a novel SRSF family-based predictive model, and we demonstrated that SRSF11 is a promising therapeutic target for HCC, which enhances our understanding of the SRSF family genes and provides valuable insights into the clinical treatment and molecular mechanisms of HCC.