Polymerase Inhibitors Research Articles

A Review on Heavy Metals in Ecosystems, Their Sources, Roles, and Impact on Plant Life

The presence of heavy metals (HMs) on Earth is essential to all forms of life. These metals are essential for plant and animal development but can have numerous negative effects on the living environment. In this review, we looked at where HMs come from, why they are harmful, and how they affect plants. Articles indexed in Google Scholar, PubMed, Research Gate, Science Direct, and a few books on heavy metals were consulted for this study. Heavy metals are essential for plant development and growth. According to this analysis, the hazardous effects of HMs are on the rise all throughout the globe, and this trend may be attributed mostly to human activity. Because of its impact on agricultural productivity and environmental changes, soil pollution caused by HMs is among the most crucial elements. Plants have evolved very sophisticated defense systems to deal with these environmental challenges. The threat that HM stress poses to plants has attracted a lot of attention worldwide because it could stunt agriculture’s long-term expansion. In spite of their importance for plants, this study found that HMs pose a significant threat to plant life. The novelty of this review lies in its detailed examination of both the beneficial and detrimental roles of HMs, providing a balanced perspective often overlooked in current literature. The significance of this work is underscored by its potential to inform sustainable agricultural practices and environmental management strategies, as it highlights the delicate balance required to harness the benefits of HMs while mitigating their risks. Despite their necessity for plant development, this review underscores the significant risks HMs pose to plant health and ecosystems.Less than 10 cases have been reported in the literature of the association of germline BRCA1 and Squamous cell Carcinoma – the esophagus. The article focuses on the probable pathogenesis of BRCA1 mutation with non-classic malignancies and the response of Poly adenosine diphosphate ribose polymerase inhibitors (PARP) inhibitors in such a scenario. We report an unusual manifestation of the BRCA1 gene with second primary oesophageal squamous cell cancer occurring five years later to triple-negative breast cancer.

Efficacy of FERscore in predicting sensitivity to ferroptosis inducers in breast cancer

Recent studies have highlighted the potential of ferroptosis in treating breast cancer. However, the efficacy of ferroptosis induction in the most common subtype, estrogen receptor-positive (ER + ) breast cancer, remains inadequately explored. This study unveils that both short-term and long-term treatment with ER-targeted endocrine agents sensitizes ER+ breast cancer cells to ferroptosis inducers, particularly the GPX4 inhibitor, revealing a non-mutational sensitization mechanism. Based on this finding, we introduce a 55-gene signature score (FERscore) tailored to assess ferroptosis susceptibility in breast cancer. Data from cell lines and primary tumors demonstrate significant lower FERscores in ER+ breast cancer compared to other subtypes; however, FERscores dramatically increase in endocrine-resistant ER+ tumor cells and residual tumors post-endocrine therapy. Furthermore, FERscore correlates positively with mesenchymal traits, stemness, immune cell infiltration, and cancer-associated fibroblasts enrichment, while inversely correlating with estrogen responsiveness and DNA repair capacity. Additionally, the FERscore proves effective in predicting therapeutic responses to anti-ER, anti-HER2, poly (ADP-ribose) polymerase inhibitor, and anti-angiogenesis therapies in breast cancer. In summary, ferroptosis induction emerges as a promising avenue in breast cancer therapy. The FERscore offers an innovative tool for identifying patients who may benefit from ferroptosis-inducing therapies, especially those responsive to GPX4 inhibitors.

Leveraging PARP-1/2 to Target Distant Metastasis.

Poly (ADP-Ribose) Polymerase (PARP) inhibitors have changed the outcomes and therapeutic strategy for several cancer types. As a targeted therapeutic mainly for patients with BRCA1/2 mutations, PARP inhibitors have commonly been exploited for their capacity to prevent DNA repair. In this review, we discuss the multifaceted roles of PARP-1 and PARP-2 beyond DNA repair, including the impact of PARP-1 on chemokine signalling, immune modulation, and transcriptional regulation of gene expression, particularly in the contexts of angiogenesis and epithelial-to-mesenchymal transition (EMT). We evaluate the pre-clinical role of PARP inhibitors, either as single-agent or combination therapies, to block the metastatic process. Efficacy of PARP inhibitors was demonstrated via DNA repair-dependent and independent mechanisms, including DNA damage, cell migration, invasion, initial colonization at the metastatic site, osteoclastogenesis, and micrometastasis formation. Finally, we summarize the recent clinical advancements of PARP inhibitors in the prevention and progression of distant metastases, with a particular focus on specific metastatic sites and PARP-1 selective inhibitors. Overall, PARP inhibitors have demonstrated great potential in inhibiting the metastatic process, pointing the way for greater use in early cancer settings.

Structural basis of paramyxo- and pneumovirus polymerase inhibition by non-nucleoside small-molecule antivirals.

Small-molecule antivirals can be used as chemical probes to stabilize transitory conformational stages of viral target proteins, facilitating structural analyses. Here, we evaluate allosteric pneumo- and paramyxovirus polymerase inhibitors that have the potential to serve as chemical probes and aid the structural characterization of short-lived intermediate conformations of the polymerase complex. Of multiple inhibitor classes evaluated, we discuss in-depth distinct scaffolds that were selected based on well-understood structure-activity relationships, insight into resistance profiles, biochemical characterization of the mechanism of action, and photoaffinity-based target mapping. Each class is thought to block structural rearrangements of polymerase domains albeit target sites and docking poses are distinct. This review highlights validated druggable targets in the paramyxo- and pneumovirus polymerase proteins and discusses discrete structural stages of the polymerase complexes required for bioactivity.

A randomized phase II study of secondary cytoreductive surgery in patients with relapsed ovarian cancer who have progressed on a PARP inhibitor as first-line maintenance therapy: the SOCCER-P study (KGOG 3067/JGOG 3036/APGOT-OV11)

BackgroundAlthough two recent phase III randomized controlled trials showed survival benefits of undergoing secondary cytoreductive surgery for an initial relapse of ovarian cancer, patients who received a poly-ADP ribose polymerase...

Physician-reported patient involvement and treatment decisions in first-line ovarian cancer in the USA and Europe

ObjectivesReal-world data evaluating how approvals of novel treatment regimens for ovarian cancer have impacted the treatment paradigm, including first-line maintenance, are lacking. This analysis aimed to describe treatment patterns for...

TEDOVA: vaccine OSE2101 +/- pembrolizumab as maintenance in platinum-sensitive recurrent ovarian cancer.

Ovarian cancer is a leading cause of death from gynecological cancers worldwide. Platinum-based chemotherapy provides the cornerstone of the medical management. In first line and subsequent relapses, maintenance strategies are offered to prolong intervals between lines of chemotherapy. Current maintenance options involve bevacizumab and poly ADP-ribose polymerase inhibitors, but these lines of therapy can only be used once in the disease course. Patients in first or second platinum sensitive relapse after poly ADP-ribose polymerase inhibitors and bevacizumab represent an area of unmet medical need. This academic sponsored, international Phase II randomized trial is evaluating the combination of a therapeutic cancer vaccine (OSE2101) with anti-PD1 (pembrolizumab) as maintenance therapy, in patients with platinum-sensitive recurrence regardless of number of prior lines and no progression after platinum-based chemotherapy.Clinical Trial Registration: NCT04713514 (ClinicalTrials.gov).

High likelihood of BRCA2 reversion mutation in pancreatic cancer post-platinum-based chemotherapy: a case study.

A 54-year-old man with resectable pancreatic cancer and abnormally high levels of carbohydrate antigen 19-9 (CA19-9) underwent 6months of platinum-based chemotherapy. This treatment substantially reduced the primary tumor size and normalized CA19-9 levels. Subsequently, radical surgery was conducted. However, eight months post-surgery, CA19-9 levels re-elevated, and lymph-node recurrence was observed. The patient underwent treatment with poly(adenosine diphosphate ribose) polymerase inhibitors (PARPi) following the detection of frameshift L1904fs*5 via BRACAnalysis CDx. This mutation revealed a stop codon, leading to the inactivation of the BRCA function. Additionally, the patient tested positive for a mutation in the breast cancer susceptibility gene 2 (BRCA2). Two months after starting PARPi, there was evidence of tumor shrinkage. Nevertheless, 5 months later, CA19-9 levels increased again, and new metastatic tumors in the liver were identified. Genomic profiling test (FoundationOne CDx) of surgically resected specimens revealed a BRCA2 pL1908fs*2 mutation, indicating its location in the cis position on the same allele as the germline BRCA2 mutation. The pL1908fs*2 deletion, alongside the original L1904fs*5, resulted in three deletions, equating to one amino acid deletion. This deletion ultimately reversed the stop codon, leading to the restoration of BRCA2 functionality. Despite treatment with PARPi for postoperative recurrence, a sustained response was not achieved owing to BRCA reversion mutations. It is essential to acknowledge the rarity of BRCA reversion mutations, which limit the effectiveness of PARPi.

Factors associated with an inconclusive result from commercial homologous recombination deficiency testing in ovarian cancer.

Homologous recombination deficiency (HRD) testing is used to determine the appropriateness of poly ADP-ribose polymerase inhibitors for patients with epithelial ovarian cancer and no germline/somatic BRCA1/2 alterations. Myriad MyChoice CDx reports a genomic instability score (GIS) to quantify the level of HRD, with a positive score defined as ≥42. The authors sought to define factors associated with obtaining an inconclusive HRD test result. GIS was retrieved for patients at their institution with epithelial ovarian cancer without germline/somatic BRCA1/2 deleterious alterations who underwent HRD testing from April 2020-August 2023. Clinical data were abstracted from the medical record. Of 477 HRD test results identified, 57 (12%) were inconclusive. High-grade serous ovarian cancers had higher GIS than other histologic types (median 29 vs. 21, p<.001). Most HRD cases were of high-grade serous histology; no cases with clear cell or endometrioid histology were HRD-positive. On univariate analysis, interval versus primary cytoreductive surgery, other specimen sources versus surgical specimens, and chemotherapy exposure were risk factors for inconclusive HRD testing. On multivariable analysis, chemotherapy exposure, and tissue source were associated with an inconclusive test result, with surgical specimens more likely to yield a conclusive result than other sources (biopsy, cytology, other). Age, stage, self-reported race, and histology were not associated with an inconclusive result. Surgical tissue was more likely to yield a conclusive HRD test result versus other sources of epithelial ovarian cancer tissue acquisition. When feasible, laparoscopic biopsy before initiation of neoadjuvant chemotherapy may increase the likelihood of obtaining interpretable HRD test results.

SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia

Though RNAi and RNA-splicing machineries are involved in regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, their precise roles in coronavirus disease 2019 (COVID-19) pathogenesis remain unclear. Herein, we show that decreased RNAi component (Dicer and XPO5) and splicing factor (SRSF3 and hnRNPA3) expression correlate with increased COVID-19 severity. SARS-CoV-2 N protein induces the autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, inhibiting miRNA biogenesis and RNA splicing and triggering DNA damage, proteotoxic stress, and pneumonia. Dicer, XPO5, SRSF3, and hnRNPA3 knockdown increases, while their overexpression decreases, N protein-induced pneumonia’s severity. Older mice show lower expression of Dicer, XPO5, SRSF3, and hnRNPA3 in their lung tissues and exhibit more severe N protein-induced pneumonia than younger mice. PJ34, a poly(ADP-ribose) polymerase inhibitor, or anastrozole, an aromatase inhibitor, ameliorates N protein- or SARS-CoV-2-induced pneumonia by restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression. These findings will aid in developing improved treatments for SARS-CoV-2-associated pneumonia.

Dissecting the Distinct Tumor Microenvironments of HRD and HRP Ovarian Cancer: Implications for Targeted Therapies to Overcome PARPi Resistance in HRD Tumors and Refractoriness in HRP Tumors.

High-grade serous tubo-ovarian cancer (HGSTOC) is an aggressive gynecological malignancy including homologous recombination deficient (HRD) and homologous recombination proficient (HRP) groups. Despite the therapeutic potential of poly (ADP-ribose) polymerase inhibitors (PARPis) and anti-PDCD1 antibodies, acquired resistance in HRD and suboptimal response in HRP patients necessitate more precise treatment. Herein, single-cell RNA and single-cell T-cell receptor sequencing on 5 HRD and 3 HRP tumors are performed to decipher the heterogeneous tumor immune microenvironment (TIME), along with multiplex immunohistochemistry staining and animal experiments for validation. HRD tumors are enriched with immunogenic epithelial cells, FGFR1+PDGFRβ+ myCAFs, M1 macrophages, tumor reactive CD8+/CD4+ Tregs, whereas HRP tumors are enriched with HDAC1-expressing epithelial cells, indolent CAFs, M2 macrophages, and bystander CD4+/CD8+ T cells. Significantly, customized therapies are proposed. For HRD patients, targeting FGFR1+PDGFRβ+ myCAFs via tyrosine kinase inhibitors, targeting Tregs via anti-CCR8 antibodies/TNFRSF4 stimulation, and targeting CXCL13+ exhausted T cells by blocking PDCD1/CTLA-4/LAG-3/TIGIT are proposed. For HRP patients, targeting indolent CAFs, targeting M2 macrophages via CSF-1/CSF-1R inhibitors, targeting bystander T cells via tumor vaccines, and targeting epithelial cells via HDAC inhibitors. The study provides comprehensive insights into HRD and HRP TIME and tailored therapeutic approaches, addressing the challenges of PARPi-resistant HRD and refractory HRP tumors.

AXL inhibition prevents RPA2/CHK1-mediated homologous recombination to increase PARP inhibitor sensitivity in hepatocellular carcinoma

Homologous recombination defects (HRD) render cells fail to repair DNA double-strand break (DSB), which causes synthetic lethality in these cells with punch by poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). Here, we reveal a receptor tyrosine kinase, AXL, whose inhibition leads to HRD in hepatocellular carcinoma (HCC) cells. AXL is upregulated in HCC tumors, which is positively correlated with low survival rates. AXL knockdown or AXL inhibition by bemcentinib reduces HR efficiency in HCC cells, and AXL plays its role in HR repair through its kinase activity. Furthermore, we find that AXL interacts with RPA2, enhancing the recruitment of RPA2 to DNA damage sites. Mechanistically, AXL promotes the tyrosinization of RPA2 at tyrosine 9, promoting the phosphorylation of CHK1, thereby strengthens the HR repair ability in HCC cells to resist DNA damage. In conclusion, our results reveal that AXL is a promising therapeutic biomarker for HCC patients, and present that targeting AXL-RPA2-CHK1 pathway together with PARP inhibitor will be effective therapeutic strategy in HCC.

Efficacy of a platinum-based chemotherapy rechallenge for platinum-sensitive recurrence after PARP inhibitor maintenance

ObjectivePlatinum-free interval (PFI) is the period from the end of platinum-based chemotherapy to the date of recurrence. If the PFI is > 6 months, a platinum-based chemotherapy rechallenge is considered; however, its efficacy after poly adenosine 5′-diphosphate-ribose polymerase (PARP) inhibitor maintenance therapy is unknown. This study aimed to examine the efficacy of a platinum-based chemotherapy rechallenge after PARP inhibitor therapy. MethodsWe retrospectively evaluated patients with ovarian cancer with a PFI≥6 months with PARP inhibitor maintenance therapy, receiving platinum-based chemotherapy. Duration of PARP inhibitor therapy, best response to subsequent platinum chemotherapy rechallenge, and clinical characteristics were collected from medical records. Tumor response was assessed according to RECIST 1.1. Correlations were calculated using Spearman’s correlation coefficients. ResultsAmong the 10 included patients, seven (70 %) received PARP inhibitors after primary chemotherapy, and three (30 %) received chemotherapy for platinum-sensitive relapse. One and five patients harbored a germline BRCA1 and BRCA wild-type mutations, respectively, and two had homologous recombination proficiency. The median PFI was 303.5 (182–602) days, and PARP inhibitor therapy duration was 249 (147–570) days. Platinum chemotherapy rechallenge efficacy was complete and partial response and stable disease in one (10 %), six (60 %), and three (30 %) patients, respectively. The longer the duration of PARP inhibitor treatment, better the response to platinum agents (Spearman correlation coefficient 0.284, p = 0.0288). ConclusionPlatinum-based chemotherapy rechallenge is reasonable for patients with platinum-sensitive disease, using the traditional PFI cutoff of 6 months, even when the PFI is obtained with a maintenance PARP inhibitor.

EHMT1/2 inhibition promotes regression of therapy-resistant ovarian cancer tumors in a CD8 T cell-dependent manner.

Poly ADP-ribose polymerase inhibitors (PARPi) are first-line maintenance therapy for ovarian cancer and an alternative therapy for several other cancer types. However, PARPi-resistance is rising and there is currently an unmet need to combat PARPi-resistant tumors. Here, we created an immunocompetent, PARPi-resistant mouse model to test the efficacy of combinatory PARPi and euchromatic histone methyltransferase 1/2 inhibitor (EHMTi) in the treatment of PARPi-resistant ovarian cancer. We discovered that inhibition of EHMT1/2 resensitizes cells to PARPi. Markedly, we show that single EHMTi and combinatory EHMTi/PARPi significantly reduced PARPi-resistant tumor burden and that this reduction is partially dependent on CD8 T cells. Altogether, our results show a low-toxicity drug that effectively treats PARPi-resistant ovarian cancer in an immune-dependent manner, supporting its entry into clinical development and potential incorporation of immunotherapy. Implications: Targeting the epigenome of therapy-resistant ovarian cancer induces an anti-tumor response mediated in part through an anti-tumor immune response.

Persistence of an infectious form of SARS-CoV-2 post protease inhibitor treatment of permissive cells in vitro.

Reports have described SARS-CoV-2 rebound in COVID-19 patients treated with nirmatrelvir, a 3CL protease inhibitor. The cause remains a mystery, although drug resistance, re-infection, and lack of adequate immune responses have been excluded. We now present virologic findings that provide a clue to the cause of viral rebound, which occurs in ∼20% of the treated cases. Persistence of infectious SARS-CoV-2 was experimentally documented in vitro after treatment with nirmatrelvir or another 3CL protease inhibitor, but not with a polymerase inhibitor, remdesivir. This infectious form decayed slowly with a half-life of ∼1 day, suggesting that its persistence could outlive the treatment course to re-ignite SARS-CoV-2 infection as the drug is eliminated. Notably, extending nirmatrelvir treatment beyond 8 days abolished viral rebound in vitro. Our findings point in a particular direction for future investigation of virus persistence and offer a specific treatment recommendation that should be tested clinically.

CDK9 inhibition constrains multiple oncogenic transcriptional and epigenetic pathways in prostate cancer

BackgroundCyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer and CDK9 inhibitors have emerged as promising therapeutic candidates.MethodsThe activity of an orally bioavailable CDK9 inhibitor, CDKI-73, was evaluated in prostate cancer cell lines, a xenograft mouse model, and patient-derived tumor explants and organoids. Expression of CDK9 was evaluated in clinical specimens by mining public datasets and immunohistochemistry. Effects of CDKI-73 on prostate cancer cells were determined by cell-based assays, molecular profiling and transcriptomic/epigenomic approaches.ResultsCDKI-73 inhibited proliferation and enhanced cell death in diverse in vitro and in vivo models of androgen receptor (AR)-driven and AR-independent models. Mechanistically, CDKI-73-mediated inhibition of RNA polymerase II serine 2 phosphorylation resulted in reduced expression of BCL-2 anti-apoptotic factors and transcriptional defects. Transcriptomic and epigenomic approaches revealed that CDKI-73 suppressed signaling pathways regulated by AR, MYC, and BRD4, key drivers of dysregulated transcription in prostate cancer, and reprogrammed cancer-associated super-enhancers. These latter findings prompted the evaluation of CDKI-73 with the BRD4 inhibitor AZD5153, a combination that was synergistic in patient-derived organoids and in vivo.ConclusionOur work demonstrates that CDK9 inhibition disrupts multiple oncogenic pathways and positions CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.

Histone-methyltransferase KMT2D deficiency impairs the Fanconi anemia/BRCA pathway upon glycolytic inhibition in squamous cell carcinoma

Histone lysine methyltransferase 2D (KMT2D) is the most frequently mutated epigenetic modifier in head and neck squamous cell carcinoma (HNSCC). However, the role of KMT2D in HNSCC tumorigenesis and whether its mutations confer any therapeutic vulnerabilities remain unknown. Here we show that KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Additionally, KMT2D loss decreases the expression of Fanconi Anemia (FA)/BRCA pathway genes under glycolytic inhibition. Mechanistically, glycolytic inhibition facilitates the occupancy of KMT2D to the promoter/enhancer regions of FA genes. KMT2D loss reprograms the epigenomic landscapes of FA genes by transiting their promoter/enhancer states from active to inactive under glycolytic inhibition. Therefore, combining the glycolysis inhibitor 2-DG with DNA crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors preferentially inhibits tumor growth of KMT2D-deficient mouse HNSCC and patient-derived xenografts (PDXs) harboring KMT2D-inactivating mutations. These findings provide an epigenomic basis for developing targeted therapies for HNSCC patients with KMT2D-inactivating mutations.

Abiraterone, Olaparib, or Abiraterone + Olaparib in First-Line Metastatic Castration-Resistant Prostate Cancer with DNA Repair Defects (BRCAAway).

Deleterious germline/somatic homologous recombination repair mutations (HRRm) are present in ∼25% of patients with metastatic castration-resistant prostate cancer (mCRPC). Preclinically, poly(ADP-ribose) polymerase (PARP) inhibition demonstrated synergism with androgen receptor pathway (ARP)-targeted therapy. This trial evaluated the efficacy of ARP inhibitor versus PARP inhibitor versus their combination as first-line therapy in patients with mCRPC with HRRms. BRCAAway is a biomarker preselected, randomized, phase 2 trial. Patients with BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm1: abiraterone (1,000 mg)/prednisone (5 mg BID) (Abi/pred), Arm2: olaparib (300 mg BID) (Ola), or Arm3: abiraterone/prednisone + olaparib (Abi/pred + Ola). Single-agent arms could cross over at progression. Exploratory Arm4 patients with other HRRms received olaparib alone. The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response, PSA response, and safety. Sixty-one of 165 eligible patients had BRCA1/2 or ATM mutations: median age: 67 (IQR, 62-73) years. Mutations: BRCA1 n = 3, BRCA2 n = 46, ATM n = 11, and multiple n = 1; 33 germline and 28 somatic mutations. Median PFS [95% confidence interval (CI)]: Abi/pred, 8.6 months (m; 2.9, 17), Ola, 14 m (8.4, 20), and Abi/pred + Ola, 39 m [22, not reached (NR)]. There were no G4/5 adverse events; 8/19 patients on Abi/pred treatment crossed over to Ola, and 8/21 vice versa. Median PFS (95% CI) from crossover: Ola-after-Abi/pred, 8.3 m (5.5, 15) and Abi/pred-after-Ola, 7.2 m (2.8, NR). Median PFS (95% CI) from randomization: Ola-after-Abi/pred, 16 m (7.8, 25) and Abi/pred-after-Ola, 16 m (11, NR). Seventeen of 165 patients with other HRRms received olaparib: median PFS (95% CI): 5.5 m (2, 11). In patients with mCRPC with BRCA1/2 or ATM HRRm, Abi/pred + Ola was well tolerated and demonstrated longer PFS versus either agent alone or sequentially.

Discovery of gem-Dimethyl-hydroxymethylpyridine Derivatives as Potent Non-nucleoside RSV Polymerase Inhibitors.

Respiratory syncytial virus (RSV) is an RNA virus infecting the upper and lower respiratory tract and is recognized as a major respiratory health threat, particularly to older adults, immunocompromised individuals, and young children. Around 64 million children and adults are infected every year worldwide. Despite two vaccines and a new generation monoclonal antibody recently approved, no effective antiviral treatment is available. In this manuscript, we present the medicinal chemistry efforts resulting in the identification of compound 28 (JNJ-8003), a novel RSV non-nucleoside inhibitor displaying subnanomolar activity in vitro as well as prominent efficacy in mice and a neonatal lamb models.

CX-5461 ameliorates disease in lupus-prone mice by triggering B-cell ferroptosis via p53-SLC7A11-ALOX12 pathway

CX-5461, a first-in-class compound, is widely recognized as a selective inhibitor of RNA polymerase I. Recently, it has been reported to possess novel immunosuppressive properties with significant therapeutic effects in transplantation immune rejection. However, the potential use of CX-5461 for Systemic Lupus Erythematosus (SLE) treatment remains unknown. In this study, we elucidated the mechanism underlying the therapeutic efficacy of CX-5461 in lupus. Our findings demonstrated that CX-5461 selectively targets B cells and effectively reduces the proportions of B cells, germinal center B cells, and plasma cells in MRL/MPJ-Faslpr and Resiquimod (R848)-induced lupus mice. Molecular studies revealed that CX-5461 modulates CD36-Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4)-mediated glycerolipid metabolism in B cells, triggering ferroptosis through the p53- Solute Carrier Family 7 Member 11 (SLC7A11)- Arachidonate 12-Lipoxygenase (ALOX12) pathway, thereby decreasing IgG and Anti-Double-Stranded Deoxyribonucleic Acid (dsDNA) antibody levels and attenuating lupus. Collectively, these results suggest that CX-5461 holds promise as an effective candidate for targeted therapy against lupus.