Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are now widely used in BRCA1/2 mutation or homologous recombination (HR) deficiency ovarian cancer but have limited efficacy in HR-proficient patients. GPX4 is a key regulator of ferroptosis and has been proven to be associated with multiple drug sensitivities. As a molecule that regulates the sensitivity of multiple drugs, the relationship between GPX4 and the efficacy of PARPi in HR-proficient ovarian cancer has not been elucidated. Methods: In this study, siRNA transfection was used to regulate the expression of GPX4. The effect of GPX4 inhibition on HR-proficient ovarian cancer was determined by CCK-8 assay and flow cytometry. Immunofluorescence and comet assays were used to reflect DNA dam-age. ROS production was measured using DCFH-DA and flow cytometry. The combination index of PARP inhibitors and RSL3 was calculated using CompuSyn software based on Chou-Talalay methodology. Results: GPX4 inhibition confers HR-proficient ovarian cancer cells sensitive to PARPi due to ROS generation and oxidative stress caused by DNA double-strand breakage. The combina-tion of olaparib and niraparib with GPX4 inhibitor RSL3 also showed a synergistic effect. Conclusion: Combining GPX4 inhibition with PARP inhibitors resulted in a notable increase in DNA damage, ultimately causing the death of cancer cells with proficient HR pathways. Our findings may provide new therapeutic options for HR-proficient patients to benefit from PARP inhibitors and improve outcomes.

In the article titled "GPX4 Inhibition Enhances the Antitumor Effect of PARP Inhibitor on Homologous Recombination Proficient Ovarian Cancer Cells", published in Current Cancer Drug Targets, 2026, 26(2), 221-230 [1], Fig no. 2, part (A) was incorrect. The original article can be found online at: https://www.benthamscience.com/issue/14684.

Hypoxia is a critical factor driving tumor invasion and metastasis. N-myc Downstream Regulated Gene 1 (NDRG1), a known suppressor of invasion and metastasis in various cancers including clear cell renal cell carcinoma (ccRCC), remains poorly understood in the context of hypoxic regulation. Notably, the carboxy terminus (C-terminus) of NDRG1 contains multiple phosphorylation sites within a unique three-tandem-repeat sequence that responds to hypoxic conditions. However, the precise regulatory mechanisms and functional significance of phosphorylation in this region remain unexplored. Our research uncovered that hypoxia triggers poly-phosphorylation at the C-terminus of NDRG1, thereby facilitating epithelial-mesenchymal transition (EMT) in ccRCC. NDRG1 knockdown alone was sufficient to induce EMT, augmenting the invasive and metastatic capabilities of ccRCC cells. Specifically, hypoxia-induced phosphorylation at the C-terminus (sites 328/330 and 346/356/366, phosphorylated by SGK1) of NDRG1 enhances its SUMOylation and ubiquitination, leading to NDRG1 degradation. NDRG1 typically forms a complex with E-cadherin and β-catenin to suppress WNT signaling; however, this complex is disrupted by phosphorylation at the 346/356/366 sites. In vivo studies demonstrated that NDRG1 knockdown expedited tumor growth and pulmonary metastasis, but the re-expression of phosphorylation-deficient mutants, particularly at sites 328/330 and 346/356/366, significantly mitigated these tumor-promoting effects. Our study demonstrates that hypoxia-induced C-terminal poly-phosphorylation of NDRG1 promotes its degradation, activating the WNT pathway and driving ccRCC malignancy. These findings underscore the role of NDRG1 phosphorylation in ccRCC progression under hypoxic conditions and highlight potential therapeutic targets for intervention.

Background:Magnetic resonance imaging (MRI) currently stands as a cornerstone in preoperative staging and detection of lymph node metastasis (LNM) in cervical cancer (CC). The objective of this study was to assess the efficacy of MRI in discerning LNM in CC. Methods:This retrospective study scrutinized patient data across three medical centers, focusing on those who underwent preoperative MRI assessment followed by radical surgery and pelvic lymph node (LN) dissection. We juxtaposed the correspondence between LN status as determined by MRI and pathological findings, conducting comprehensive data analysis through statistical software. In addition, the factors that may lead to misinterpretation of MRI were analyzed. Results:Out of a cohort comprising 1,027 patients, 10.9% (112/1,027) exhibited LN positivity on MRI, with 49.1% (55/112) confirmed as LNM upon pathological examination. Among patients with negative MRI findings, around 15.7% (144/915) were later diagnosed with LNM. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MRI for assessing LNM were determined to be 27.6%, 93.0%, 49.1%, and 84.3%, respectively. LNM in CC patients is associated with MRI findings, squamous cell carcinoma antigen (SCCA), carbohydrate antigen 125 (CA125), and carcinoembryonic antigen (CEA). The SCCA level of the misjudgment group was significantly higher than that of the accurate group. Conclusions:Preoperative MRI exhibits limitations in sensitivity and accuracy when discerning metastatic from non-metastatic LNs in CC. Therefore, categorizing patients as stage IIIC solely based on MRI-detected LN positivity warrants further scrutiny.

The role of the gut microbiota in the occurrence and progression of primary biliary cholangitis (PBC) is not fully understood. First, the fecal microbiota of patients with PBC (n = 4) (PBC-FMT) or healthy individuals (n = 3) (HC-FMT) was transplanted into pseudo germ-free mice or 2OA-BSA-induced PBC models. The functions, histology and transcriptome of the liver, and microbiota and metabolome of the feces were analyzed. Second, the liver transcriptomes of PBC patients (n = 7) and normal individuals (n = 7) were analyzed. Third, the liver transcriptomes of patients with other liver diseases were collected from online databases and compared with our human and mouse data. Our results showed that PBC-FMT increased the serum ALP concentration, total bile acid content, liver injury and number of disease-related pathways enriched with upregulated liver genes in pseudo germ-free mice and increased the serum glycylproline dipeptidyl aminopeptidase level and liver damage in a 2OA-BSA-induced PBC model. The gut microbiota and metabolome differed between PBC-FMT and HC-FMT mice and reflected those of their donors. PBC-FMT tended to upregulate hepatic immune and signal transduction pathways but downregulate metabolic pathways, as in some PBC patients. The hematopoietic cell lineage, Toll-like receptor, and PPAR signaling pathway were not affected in patients with alcoholic hepatitis, HBV, HCV, HCV cirrhosis, or NASH, indicating their potential roles in the gut microbiota affecting PBC. In conclusion, the altered gut microbiota of PBC patients plays an important role in the occurrence and progression of PBC. The improvement of the gut microbiota is worthy of in-depth research and promotion as a critical aspect of PBC prevention and treatment.

Introduction Ovarian cancer is the most lethal gynecological cancer and presents significant therapeutic challenges. The discovery of synthetic lethality between PARP inhibitors (PARPi) and homologous recombination deficiency marked a new era in treating BRCA1/2-mutated tumors. However, PARPi resistance remains a major clinical challenge. Methods RNA sequencing was used to identify genes altered by PARPi treatment and LC-MS was used to detect proteins interacting with CYP1B1. Resistance mechanisms were explored through ATAC-seq and gene expression manipulation. Additional techniques, including micrococcal nuclease digestion assays, DAPI staining, and fluorescence microscopy, were used to assess changes in nuclear morphology and chromatin accessibility. Results The gradual exposure of Olaparib has developed a PARPi-resistant cell line, A2780-OlaR, which exhibits significant upregulation of CYP1B1 at both RNA and protein levels. Down-regulating CYP1B1 expression or using specific inhibitors decreased the cellular response to Olaparib. Linker histone H1.4 was identified as associated with CYP1B1. ATAC-seq showed differential chromatin accessibility between A2780-OlaR and parental cells, indicating that the downregulation of H1.4 was associated with increased chromatin accessibility and higher cell viability after Olaparib treatment. Conclusion Our findings reveal a novel role for CYP1B1 in driving PARPi resistance through distinct molecular mechanisms in A2780-OlaR. This study highlights the importance of chromatin accessibility in PARPi efficacy and suggests the CYP1B1/H1.4 axis as a promising therapeutic target for overcoming drug resistance in ovarian cancer, offering potentially therapeutic benefits.

The phosphorylation of histone H2A.X into γH2A.X is a crucial early event in the DNA damage response, marking DNA damage sites and initiating repair processes. While ATM kinase is traditionally recognized as the primary mediator of H2A.X phosphorylation, our study identifies serine/threonine kinase 39 (STK39) as a novel enhancer of this critical signaling pathway. We demonstrate that after DNA damage, STK39 undergoes phosphorylation by the ATM kinase, facilitating its interaction with the Mre11-Rad50-Nbs1 complex and subsequent recruitment to chromatin. This recruitment enables STK39 to further phosphorylate H2A.X, thus amplifying γH2A.X production and promoting homologous recombination repair. Notably, we observe a significant upregulation of STK39 in pancreatic adenocarcinoma (PAAD) tissues, correlating with heightened resistance to PARPi therapy. Furthermore, we demonstrate the synergistic efficacy of combining STK39 inhibition with PARP inhibitors in suppressing and reversing PAAD growth. This study not only provides new insights into the molecular dynamics of H2A.X phosphorylation but also highlights the therapeutic potential of targeting STK39 to enhance PARPi sensitivity in PAAD (created with BioRender).

METi treatment significantly boosted CD8+ cytotoxic T cells and NK infiltration in MET OE tumors

Single-cell RNA-seq reveals the distinctive functional composition of immune cells in MET amplification patients

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination (HR) deficiency. However, many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin. The biomarker responsible for this mechanism remains unclear. Here, we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients. PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage (ATM) signaling-induced pro-apoptotic ribosomal stress, which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage. Therefore, the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin. The gene panel as an independent biomarker was validated by multiple published clinical datasets, as well as by an ovarian cancer organoids library we established. More importantly, its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data. Furthermore, we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines. These drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired resistance. Together, our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy.

Liver transplantation (LT) is the final treatment option for patients with end-stage liver disease. The increasing donor shortage results in the wide usage of grafts from extended criteria donors across the world. Using such grafts is associated with the elevated incidences of post-transplant complications including initial nonfunction and ischemic biliary tract diseases, which significantly reduce recipient survival. Although several clinical factors have been demonstrated to impact donor liver quality, accurate, comprehensive, and effective assessment systems to guide decision-making for organ usage, restoration or discard are lacking. In addition, the development of biochemical technologies and bioinformatic analysis in recent years helps us better understand graft injury during the perioperative period and find potential ways to restore graft function. Moreover, such advances reveal the molecular profiles of grafts or perfusate that are susceptible to poor graft function and provide insight into finding novel biomarkers for graft quality assessment. Focusing on donors and grafts, we updated potential biomarkers in donor blood, liver tissue, or perfusates that predict graft quality following LT, and summarized strategies for restoring graft function in the era of extended criteria donors. In this review, we also discuss the advantages and drawbacks of these potential biomarkers and offer suggestions for future research.

Endometrial cancer is the most common gynecological malignancy, affecting up to 3% of women at some point during their lifetime (Morice et al., 2016; Li and Wang, 2021). Based on the pathogenesis and biological behavioral characteristics, endometrial cancer can be divided into estrogen-dependent (I) and non-estrogen-dependent (II) types (Ulrich, 2011). Type I accounts for approximately 80% of cases, of which the majority are endometrioid carcinomas, and the remaining are mucinous adenocarcinomas (Setiawan et al., 2013). It is generally recognized that long-term stimulation by high estrogen levels with the lack of progesterone antagonism is the most important risk factor; meanwhile, there is no definite conclusion on the specific pathogenesis. The incidence of endometrial cancer has been on the rise during the past two decades (Constantine et al., 2019; Gao et al., 2022; Luo et al., 2022). Moreover, the development of assisted reproductive technology and antiprogestin therapy following breast cancer surgery has elevated the risk of developing type I endometrial cancer to a certain extent (Vassard et al., 2019). Therefore, investigating the influence of estrogen in type I endometrial cancer may provide novel concepts for risk assessment and adjuvant therapy, and at the same time, provide a basis for research on new drugs to treat endometrial cancer.

MET regulates STING expression by UPF1

Abstract Background Salpingotomy may change the anatomical structure and patency of the fallopian tube, which may affect the fallopian function. This study is to investigate the clinical efficacy of preliminary hysteroscopic tubal hydrotubation (HTH) after laparoscopic salpingotomy for tubal ampullary pregnancy. Methods A retrospective study was carried out, 140 women underwent laparoscopic salpingotomy for ampullary pregnancy from March 2013 to March 2017. Some patients received HTH in the 1st month and hysterosalpingography (HSG) in the 3rd month after salpingotomy (HTH group; n = 95), and some patients only received HSG in the 3rd month after salpingotomy (control group; n = 45). Clinical data, tubal patency and fertility outcome were evaluated after follow-up of 15 months. Results The tubal patency rate of the operated side was significantly higher in the HTH group than that in the control group (89.47% vs 68.89%, P < 0.05). The intrauterine pregnancy (IUP) rate was significantly higher in the HTH group (76.47% vs 51.11%, P < 0.05), and the recurrent ectopic pregnancy rate in the operated side was significantly lower in the HTH group than in the control group (9.41% vs 22.22%, P < 0.05). Logistic regression analysis showed that the positive factor for IUP was HTH (OR = 3.109, 95% CI 1.439–6.714, P = 0.004), while the negative factors were history of pelvic inflammatory disease (PID) (OR = 0.167, 95% CI 0.074–0.377, P < 0.001) and history of tubal infertility (OR = 0.286, 95% CI 0.113–0.723, P < 0.05). Conclusion Preliminary HTH after laparoscopic salpingotomy for ampullary pregnancy could improve reproductive function and lead to a better fertility outcome. Patients without history of PID or tubal infertility may be the most suitable ones for HTH after salpingotomy.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Characterization of genetic alterations will improve our understanding and therapies for this disease. Here, we report that PDAC with elevated expression of METTL16, one of the 'writers' of RNA N6-methyladenosine modification, may benefit from poly-(ADP-ribose)-polymerase inhibitor (PARPi) treatment. Mechanistically, METTL16 interacts with MRE11 through RNA and this interaction inhibits MRE11's exonuclease activity in a methyltransferase-independent manner, thereby repressing DNA end resection. Upon DNA damage, ATM phosphorylates METTL16 resulting in a conformational change and autoinhibition of its RNA binding. This dissociates the METTL16-RNA-MRE11 complex and releases inhibition of MRE11. Concordantly, PDAC cells with high METTL16 expression show increased sensitivity to PARPi, especially when combined with gemcitabine. Thus, our findings reveal a role for METTL16 in homologous recombination repair and suggest that a combination of PARPi with gemcitabine could be an effective treatment strategy for PDAC with elevated METTL16 expression.

Abstract Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 patients with lung cancer under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progression-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T-cell infiltration. Furthermore, we performed deep single-cell RNA sequencing on more than 20,000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted natural killer (NK) cells and decreased CD8+ T-cell and NK-cell populations in patients with MET amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3′-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET. Significance: We suggest that the combination of MET inhibitor together with ICB will overcome ICB resistance induced by MET amplification. Our report reveals much-needed information that will benefit the treatment of patients with primary MET amplification or EGFR–tyrosine kinase inhibitor resistant-related MET amplification. This article is highlighted in the In This Issue feature, p. 2659

SummaryMillions of people die from liver diseases annually, and liver failure is one of the three major outcomes of liver disease. The gut microbiota plays a crucial role in liver diseases. This study aimed to explore the effects of Lactobacillus casei strain Shirota (LcS), a probiotics used widely around the world, on acute liver injury (ALI), as well as the underlying mechanism. Sprague Dawley rats were intragastrically administered LcS suspensions or placebo once daily for 7 days before induction of ALI by intraperitoneal injection of D‐galactosamine (D‐GalN). Histopathological examination and assessments of liver biochemical markers, inflammatory cytokines, and the gut microbiota, metabolome and transcriptome were conducted. Our results showed that pretreatment with LcS reduced hepatic and intestinal damage and reduced the elevation of serum gamma‐glutamyltranspeptidase (GGT), total bile acids, IL‐5, IL‐10, G‐CSF and RANTES. The analysis of the gut microbiota, metabolome and transcriptome showed that LcS lowered the ratio of Firmicutes to Bacteroidetes; reduced the enrichment of metabolites such as chenodeoxycholic acid, deoxycholic acid, lithocholic acid, d‐talose and N‐acetyl‐glucosamine, reduce the depletion of d‐glucose and l‐methionine; and alleviated the downregulation of retinol metabolism and PPAR signalling and the upregulation of the pyruvate metabolism pathway in the liver. These results indicate the promising prospect of using LcS for the treatment of liver diseases, particularly ALI.

The present study evaluates the value of mitochondrial antiviral signaling (MAVS) expression as a potential diagnostic biomarker and therapeutic target for ovarian cancer (OC) and analyses the underlying biological mechanism in this pathology. First, the association between MAVS expression determined by immunohistochemical (IHC) and clinical characteristics was systematically investigated. Overexpression of MAVS was associated with advanced clinical factors and poor survival of OC patients. Second, bioinformatics analyses, namely, gene expression, mutation analysis, gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and weighted gene co-expression network analysis (WGCNA), were performed to evaluate the potential biological functions of MAVS in OC. The results showed that MAVS may play a critical role in immune cell infiltration. CIBERSORT was applied to assess the infiltration of immune cells in OC. CD8+ T cells, γδT cells, and eosinophils had significantly negative correlations with MAVS expression. Finally, sensitivity analysis found that patients with high MAVS expression were predicted to be significantly less responsive to cisplatin and paclitaxel. In conclusion, these findings suggested that MAVS influences biological behavior by regulating the immune response and that it can be used as a predictive marker for poor prognosis in OC.

AbstractPARP inhibitors induce DNA lesions, the repair of which are highly dependent on homologous recombination (HR), and preferentially kill HR‐ deficient cancers. However, cancer cells have developed several mechanisms to transform HR and confer drug resistance to PARP inhibition. Therefore, there is a great clinical interest in exploring new therapies that induce HR deficiency (HRD), thereby sensitizing cancer cells to PARP inhibitors. Here, we found that GSK2578215A, a high‐selective and effective leucine‐rich repeat kinase 2 (LRRK2) inhibitor, or LRRK2 depletion suppresses HR preventing the recruitment of RAD51 to DNA damage sites through disruption of the interaction of RAD51 and BRCA2. Moreover, LRRK2 inhibition or depletion increases the susceptibility of ovarian cancer cells to Olaparib in vitro and in vivo. In clinical specimens, LRRK2 high expression is high related with advanced clinical characteristics and poor survival of ovarian cancer patients. All these findings indicate ovarian cancers expressing high levels of LRRK2 are more resistant to treatment potentially through promoting HR. Furthermore, combination treatment with an LRRK2 and PARP inhibitor may be a novel strategy to improve the effectiveness of LRRK2 expression ovarian cancers.

Liver failure is a serious hepatic dysfunction with high mortality. This work aimed to investigate the effect of a famous probiotic and drug, Lactobacillus reuteri DSM 17938, on liver failure in rats. Sprague-Dawley rats were gavaged with 3 × 109 CFU of DSM 17938 for 7 days. d-galactosamine was intraperitoneally injected to induce acute liver failure on the eighth day. Samples were collected to determine the liver function, serum cytokines levels, terminal ileum and liver histology, gut microbiota, metabolome and transcriptome. Our results showed that pretreatment with DSM 17938 not only reduced the elevation in serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, IL-1α, IL-2, IL-18, M-CSF, and MIP-3α levels but also alleviated histological abnormalities of both the terminal ileum and liver induced by d-galactosamine. Additionally, DSM 17938 reduced d-galactosamine-induced enrichment of some taxa of gut Actinobacteria or Firmicutes, including abundant pathogens such as Actinomycetales, Coriobacteriaceae, Staphylococcaceae and Enterococcaceae. Furthermore, DSM 17938 reduced the d-galactosamine-induced increase in not only fecal metabolites such as trisaminol and lithocholic acid but also the transcription of liver inflammatory genes, such as Ccl2, Ccl7, Ccl11, Ccl12, Il6, Il11, Il20rb, Mmp3 and Mmp10. Downregulation of retinol metabolism and PPAR signaling pathway as well as upregulation of viral protein interaction with cytokine and cytokine receptor and central carbon metabolism in cancer signaling pathway were involved in the mechanism of L. reuteri DSM 17938 alleviating liver failure. Our findings suggested that DSM 17938 is a potential probiotic for the prevention or treatment of liver failure.