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MIR17HG, located on chromosome 13, is a class of Pri-miRNAs that generates six miRNAs: miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1 and miR-92-1. These miRNAs are ubiquitously overexpressed in diverse tumour types and exhibit complex biological links to tumour metastasis. We demonstrated that MIR17HG-derived miR-18a and miR-19a coordinately mediate gastric cancer cell metastasis by directly inhibiting SMAD2 expression and upregulating Wnt/β-catenin signalling. Based on previous studies, we hypothesised that an investigation of MIR17HG inhibition would be beneficial to clinical gastric cancer treatment, and systematically coupled bioinformatics analyses brought interferon regulatory factor-1 (IRF-1) to our attention. We then established stable clones in gastric cancer cells containing a doxycycline-inducible IRF-1 expression system and found that the expression of IRF-1 downregulates the embedded miRNAs of MIR17HG in gastric cancer cells and inhibits gastric cancer cell metastasis by attenuating Wnt/β-catenin signalling. Further rescue assays confirmed the crucial roles of miR-18a and miR-19a in the IRF-1-mediated inhibition of Wnt/β-catenin signalling. We also demonstrated that IRF-1 binds to the transcriptional site in the MIR17HG promoter and inhibits MIR17HG expression. Moreover, IFN-γ induced the IRF-1-mediated downregulation of MIR17HG in gastric cancer cells. Our hypothesis was supported by the results of immunohistochemistry analyses of clinical gastric cancer samples, and we also demonstrated the role of IRF-1 in inhibiting MIR17HG expression and tumour metastasis in vivo. We conclude that IRF-1 inhibits gastric cancer metastasis by downregulating MIR17HG-miR-18a/miR-19a axis expression and attenuating Wnt/β-catenin signalling.

Background Portal hypertension (PHT) has been proven to be closely related to the development of hepatocellular carcinoma (HCC). Whether PHT before liver transplantation (LT) will affect the recurrence of HCC is not clear. Methods 110 patients with depressurization of the portal vein (DPV) operations (Transjugular Intrahepatic Portosystemic Shunt—TIPS, surgical portosystemic shunt or/and splenectomy) before LT from a HCC LT cohort, matched with 330 preoperative non-DPV patients; this constituted a nested case-control study. Subgroup analysis was based on the order of DPV before or after the occurrence of HCC. Results The incidence of acute kidney injury and intra-abdominal bleeding after LT in the DPV group was significantly higher than that in non-DPV group. The 5-year survival rates in the DPV and non-DPV group were 83.4% and 82.7% respectively ( P  = 0.930). In subgroup analysis, patients in the DPV prior to HCC subgroup may have a lower recurrence rate (4.7% vs.16.8%, P  = 0.045) and a higher tumor free survival rate (88.9% vs.74.4%, P  = 0.044) after LT under the up-to-date TNMI–II stage, while in TNM III stage, there was no difference for DPV prior to HCC subgroup compared with the DPV after HCC subgroup or the non-DPV group. Conclusion Compared with DPV after HCC, DPV treatment before HCC can reduce the recurrence rate of HCC after early transplantation (TNM I-II). DPV before LT can reduce the recurrence of early HCC.

Molecular targeted therapy has shown potential in hepatocellular carcinoma (HCC) patients, and immunotherapy applications are developing rapidly. However, clinical guidance for making individualized therapy decisions for HCC patients remains lacking. MDH (Medication Decision in HCC) gene signatures comprising 70 genes were screened using transcriptomic data from multikinase inhibitor (TKI)-resistant HCC cells and HCC patient-derived xenograft model (PDX) models. Four MDH subtypes with distinct biological and clinical characteristics were defined by unsupervised cluster analysis of HCC data from The Cancer Genome Atlas (TCGA) database. To facilitate individualized and reasonable clinical guidance for each HCC patient, we constructed the MDH score. Comprehensive analysis suggested high MDH scores were associated with TKI resistance, a high proportion of stromal cell infiltration and poor survival outcomes. We recommend concomitant stromal activity intervention and immunotherapy for this type of HCC. Moreover, low MDH scores indicate TKI sensitivity, and a combination of targeted and immunotherapy is recommended. The nomogram constructed by iteration least absolute shrinkage and selection operator (LASSO) Cox regression analysis successfully predicted 3- or 5-year survival outcomes and mortality risks of HCC patients. In conclusion, TKI resistance model-based MDH gene signatures provide novel insight into potential mechanisms of drug resistance and heterogeneity in HCC. Integrative analysis plus a simplified decision model may aid personalized treatment and prognostic assessment among HCC patients.

Recipients often suffer from hyperlactatemia during liver transplantation (LT), but whether hyperlactatemia exacerbates hepatic ischemia‐reperfusion injury (IRI) after donor liver implantation remains unclear. Here, the role of hyperlactatemia in hepatic IRI is explored. In this work, hyperlactatemia is found to exacerbate ferroptosis during hepatic IRI. Lactate‐primed lysine acetyltransferase 8 (KAT8) is determined to directly lactylate mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) at Lys100 and augments PCK2 kinase activity. By using gene‐edited mice, evidence indicating that PCK2 exacerbates hepatic ferroptosis during IRI is generated. Mechanistically, PCK2 lactylate at Lys100 acts as a critical inducer of ferroptosis during IRI by competitively inhibiting the Parkin‐mediated polyubiquitination of 3‐oxoacyl‐ACP synthase (OXSM), thereby leading to metabolic remodeling of mitochondrial fatty acid synthesis (mtFAS) and the potentiation of oxidative phosphorylation and the tricarboxylic acid cycle. More importantly, targeting PCK2 is demonstrated to markedly ameliorate hyperlactatemia‐mediated ferroptosis during hepatic IRI. Collectively, the findings support the use of therapeutics targeting PCK2 to suppress hepatic ferroptosis and IRI in patients with hyperlactatemia during LT. Recipients often suffer from hyperlactatemia during liver transplantation (LT). This study discovers that lactate‐primed KAT8 directly lactylates mitochondrial PCK2 at Lys100 (PCK2K100lac). PCK2K100lac acts as a critical inducer of ferroptosis during ischemia‐reperfusion injury (IRI) by competitively inhibiting the Parkin‐mediated polyubiquitination of OXSM, thereby leading to metabolic remodeling of mitochondrial fatty acid synthesis. This process interprets hyperlactatemia‐mediated ferroptosis during hepatic IRI.

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. 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 Given that prioritization for liver transplantation (LT) is based primarily on the model for end-stage liver disease (MELD) scores, patients with lower MELD scores, who experience chronic anemia and recurrent hypotension due to gastrointestinal bleeding (GIB), tend to be marginalized. Methods A total of 581 patients with no evidence of acute kidney injury (AKI) or chronic kidney disease 2 months before LT constituted a retrospective cohort. Within this cohort, a nested case–control study was conducted that included 134 patients with preoperative GIB (GIB(+)) and 246 matched patients without preoperative GIB (GIB(−)). A subgroup analysis was conducted based on the occurrence of AKI (AKI(− /+)) within 2 months prior to LT. Results The incidence of preoperative AKI was significantly higher in patients with GIB(+) compared with patients with GIB(−) (14.9% vs 8.1%, P =0.039), along with higher rates of postoperative complications and prolonged hospital stay; however, long-term survival rates were similar between the two groups. Subgroup analysis also revealed that the postoperative incidence of AKI and mortality rates at 60 days were elevated in patients with preoperative GIB(+) AKI(+) compared with patients with GIB(+) AKI(−). Furthermore, 5-year survival rates were significantly lower for patients with GIB(+) AKI(+) (65.0% vs 82.5%, P  = 0.040). However, no significant difference was observed between the two subgroups of AKI(+) (GIB(+) versus GIB(−)) and the two subgroups of AKI(−) in relation to postoperative complications, short-term mortality, and long-term survival rates. Conclusions Patients who experience preoperative GIB face an elevated risk of developing AKI, which is significantly correlated with a poorer prognosis for LT. A more proactive approach is needed to assess the transplant priority of patients with GIB on the waiting list.

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.

Drug resistance is a primary cause of chemotherapeutic failure; however, how this resistance develops is complex. A comprehensive understanding of chemotherapeutic resistance mechanisms may aid in identifying more effective drugs and improve the survival rates of patients with cancer. Insulin-like growth factor 1 receptor (IGF1R), a member of the insulin receptor family, has been extensively assessed for biological activity, and its putative contribution to tumor cell development and progression. Furthermore, researchers have attended to drugs that target IGF1R since IGF1R functions as a membrane receptor. However, how IGF1R participates in chemotherapeutic resistance remains unclear. Therefore, the present study described the IGF1R gene and its associated signaling pathways, and offered details of IGF1R-induced tumor chemoresistance associated with promoting cell proliferation, inhibition of apoptosis, regulation of ATP-binding cassette transporter proteins and interactions with the extracellular matrix. The present study offered additional explanations for tumor chemotherapy resistance and provided a theoretical basis of IGF1R and its downstream pathways for future possible chemotherapy treatment options.

Flexible memristor devices based on plastic substrates have attracted considerable attention due to their applications in wearable computers and integrated circuits. However, most plastic-substrate memristors cannot function or be grown in high-temperature environments. In this study, scotch-tape-exfoliated mica was used as the flexible memristor substrate in order to resolve these high-temperature issues. Our TiN/ZHO/IGZO memristor, which was constructed using a thin （10 μm） mica substrate, has superior flexibility and thermostability. After bending it 103 times, the device continues to exhibit exceptional electrical characteristics. It can also be implemented for transitions between high and low resistance states, even in temperatures of up to 300 ℃. More importantly, the biological synaptic characteristics of paired-pulse facilitation/depression （PPF/PPD） and spike- timing-dependent plasticity （STDP） were observed through applying different pulse measurement modes. This work demonstrates that flexible memristor devices on mica substrates may potentially allow for the realization of high-temperature memristor applications for biologically-inspired computing systems.

The DEAD‐box RNA helicase (DDX) family is one of the canonical splicing regulators, engaged in RNA metabolism, and generally participates in forming spliceosomes. However, systematic analysis of DDX family members in hepatocellular carcinoma (HCC) has not been conducted before, and their biological functions need to be investigated further. Based on biological function enrichment analysis, radiosensitivity index (RSI), and prediction IC50 index for sorafenib, we ultimately ascertain DDX42 as a candidate gene. DDX42 was highly expressed in HCC than in para‐tumour tissues and was a prognostic factor for HCC patients. Importantly, DDX42 overexpression promotes cell proliferation, radio‐resistance and sorafenib resistance in HCC cells and activates the PI3K/AKT pathway. Knockdown of DDX42 moderately inhibited cell growth of HCC cells and significantly increased radio‐sensitivity, enhanced the efficacy of sorafenib, and inactivated the PI3K/AKT pathway. Mechanically, DDX42 could urge the mRNA maturation of GRB2, contributing to cell proliferation and enhancement of resistance ability to radiotherapy and sorafenib for HCC cells. Subcutaneous xenograft nude mouse model showed that DDX42 significantly promoted tumour growth as compared to the control group and lifted the expression of GRB2, KI‐67 and PCNA in vivo. In conclusion, our findings facilitate the acknowledgment of tumour initiation and mechanisms of treatment resistance in HCC, and targeting the axis of DDX42 and GRB2 may be promising strategies for synergy with radiotherapy or sorafenib for HCC patients.