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.

Pancreatic ductal adenocarcinoma (PDAC) exhibits a dismal prognosis, with limited therapeutic options beyond first-line chemotherapy. Extracellular signal-regulated kinase 5 (ERK5) represents a compelling therapeutic target, particularly due to its compensatory role in sustaining proliferation and MYC stability following ERK1/2 inhibition in KRAS-mutant PDAC. To address the need for novel inhibitors, we implemented an integrated virtual screening workflow combining PSICHIC screening, KarmaDock, similarity analysis, molecular clustering, and manual selection. This strategy identified four structurally distinct ERK5-targeting candidates. Among these, compounds 1 and 2 inhibited ERK5 kinase activity with IC50 values of 416.4 and 991.3 nM, respectively. Compound 1 demonstrated potent antiproliferative effects on PDAC cell lines (PANC-1: IC50 = 1199.0 nM; MiaPaCa-2: IC50 = 62.5 nM; AsPC-1: IC50 = 199.9 nM). Molecular dynamics simulations revealed stabilization of the ERK5-compound 1 complex through hydrogen bonding with hinge residues MET-96 and ASP-94. These results establish compound 1 as a promising lead compound, providing a novel chemical scaffold for the development of ERK5-targeted therapies against PDAC.

Targeting leucine-rich repeat kinase 2 (LRRK2) has emerged as a promising strategy for the treatment of Parkinson’s disease (PD). Here, we report the identification of newly identified LRRK2 inhibitors using a multi-stage virtual screening strategy that integrates molecular docking, AI-driven predictive modeling, molecular dynamics (MD) simulations, and binding free energy change (ΔΔG) calculations. A library of 8,617 drug-like small molecules was screened, and ΔΔG analysis was subsequently used as a post-screening prioritization step to identify candidates predicted to maintain or enhance binding affinity against the pathogenic G2019S mutant. Notably, compound 3 exhibited an IC50 value of 14.21 nM against the wild-type (WT) and 14.75 nM against the G2019S mutant, along with a preliminary kinase selectivity in profiling assays. MD simulations further revealed key interaction profiles that stabilize compound binding within the active sites of both WT and G2019S LRRK2. These findings underscore the utility of integrating AI-enhanced virtual screening with ΔΔG-based post-screening prioritizationto identify mutation-resilient inhibitors, offering a robust foundation for further optimization and therapeutic development in PD.

Cholesterol metabolic reprogramming is an emerging vulnerability in cancer, yet clinical progress has been limited by a lack of druggable targets. Here, we identify the sterol-sensing domain (SSD) of SCAP as a target in gastric cancer (GC), with multi-omics confirming tumor-specific SCAP overexpression, poor prognosis, and hyperactivated synthesis. Using SSD structure-based high-throughput screening, we discovered that the natural compound Platycodin D (PD) is a small-molecule inhibitor of SCAP. PD sustains SREBP2 activation yet paradoxically blocks cholesterol efflux. The underlying mechanism is that PD specifically disrupts SCAP's sterol-sensing function, thereby permitting unrestrained SREBP2-mediated biosynthesis. This critical dysfunction leads to pathological cholesterol overload in the endoplasmic reticulum (ER), inducing proteotoxic stress. Consequently, this stress disrupts Nrf1 ER retention and forces nuclear translocation, thereby compromising LXR-mediated efflux. We further demonstrate that this SCAP targeting initiates GPX4 cascade-mediated ferroptosis, which was reversible by inhibiting cholesterol synthesis or the stress response. PD demonstrated potent tumor suppression with a significantly improved safety profile compared to cisplatin in vivo. Our work establishes a causal link between SSD disruption and ferroptotic death via cholesterol dysregulation, introducing a novel paradigm for exploiting metabolic vulnerabilities in GC therapy.

The discovery of CAP-Gly domain-containing linker protein 1(CLIP1)-Leukocyte tyrosine kinase (LTK) as an oncogenic fusion reveals a unique dependency not only on LTK kinase activity but also on CLIP1-mediated multimerization, a noncatalytic function that drives oncogenic signaling. While this fusion is currently targeted with anaplastic lymphoma kinase inhibitors, their exclusive focus on kinase inhibition leaves the scaffolding function intact, necessitating a complete protein clearance strategy. Here, we report the AI-guided development of a first-in-class proteolysis-targeting chimera (PROTAC) designed to selectively degrade the CLIP1-LTK fusion protein. By integrating deep learning models for ternary complex prediction with structure-based molecular optimization, we designed DCL05, an orally bioavailable degrader of CLIP1-LTK fusion protein, achieving picomolar degradation potency (DC50 = 40 pM) and robust antitumor activity. DCL05 consistently outperformed existing kinase inhibitors across a broad spectrum of LTK resistance-associated mutations, both in vitro and in vivo. Collectively, our study explores resistance-associated contexts of LTK and establishes a structure-guided PROTAC development pipeline, providing a promising therapeutic strategy for overcoming acquired resistance in kinase-driven cancers.

Carbonic anhydrase IX (CAIX), which is overexpressed in tumor cells under hypoxic stress, is a promising target for cancer diagnosis and therapy. To enhance tumor uptake and pharmacokinetics, we designed a series of new bivalent CAIX-targeting probes by integrating a hypoxia-sensitive 2-nitroimidazole moiety into the DPI-4452 scaffold. Among these, the new agent [68Ga]Ga-IPM-N001 demonstrated superior higher tumor uptake and significantly improved tumor-to-background ratios (T/K and T/L > 5.0) in the PET/CT imaging studies using OS-RC-2 tumor-bearing mice. This probe also exhibited rapid clearance from the gallbladder, intestines, and kidneys while maintaining strong and prolonged tumor retention, thereby limiting potential systemic toxicity in the normal tissues. Surface plasmon resonance analysis further demonstrated that the precursor IPM-N001 possesses a comparable or improved CAIX-binding affinity relative to DPI-4452. These findings indicate that this nitroimidazole-containing bivalently targeted agent holds promise as a candidate for the theranostics of clear cell renal cell carcinoma.

Acute pancreatitis (AP) is a severe inflammatory disorder with limited therapeutic options. Novel bile acids have emerged as potent immunomodulators, but the function of norcholic acid (NorCA) previously remained unknown. In this study, we identified NorCA’s role as a novel immunomodulator that alleviates acute pancreatitis through peroxisome proliferator-activated receptor α (PPARα)-mediated macrophage reprogramming and efferocytosis. Targeted metabolomics was performed on serum from patients with AP and caerulein-induced AP mice. The functional role and mechanism of NorCA were investigated using flow cytometry, immunofluorescence, efferocytosis assays, and network pharmacology, both in vitro and in vivo. Our findings indicate that NorCA levels were significantly elevated in both patients and mice with AP, correlating with disease severity and complications. NorCA treatment markedly reduced serum amylase/lipase and pancreatic histopathological damage in AP mice. Mechanistically, NorCA promoted M1-to-M2 macrophage reprogramming and enhanced efferocytosis of apoptotic cells. These effects were dependent on PPARα activation, as demonstrated by siRNA silencing and pharmacological antagonism. These findings position NorCA as a promising therapeutic candidate and severity-associated metabolite in AP.

Bromodomain-containing protein 9 (BRD9) has emerged as an epigenetic target in hematologic malignancies. However, previous studies on BRD9 PROTACs reported MYC upregulation following chronic administration. Here, we describe bifunctional BRD9 PROTAC/immunomodulatory drug (IMiD) degraders engineered to simultaneously eliminate BRD9 and IKZF1. Utilizing ternary complex modeling and structure–activity relationship (SAR) analysis, aromatic linkers and modified E3 ligands facilitated efficient degradation. The lead candidate, B8, induces potent and selective degradation of both BRD9 (DC50 = 57 pM) and IKZF1 (DC50 = 62 pM). B8 showed broad antiproliferative activity across hematologic malignancy cells, particularly lymphomas. In the OCI-ly10 xenograft model, B8 achieved near-complete tumor regression (TGI > 99%), significantly outperforming the selective BRD9 PROTAC E5 (TGI = 31%), without detectable toxicity or MYC upregulation. These findings validate this dual-targeting PROTAC/IMiD strategy as an effective approach to overcoming the limitations of selective BRD9 degraders, underscoring its therapeutic potential in hematologic malignancies.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, particularly in the presence of liver metastases. The mechanisms by which metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), influences PDAC progression and metastasis remain poorly understood. This study investigates the role of MASLD in fostering an immunosuppressive microenvironment conducive to PDAC liver metastases and identifies the macrophage migration inhibitory factor (MIF)-CD44 axis as a key mediator of this process. Utilizing data from the UK Biobank (450,754 participants, median follow-up 14.5 years), we observed an overall increased risk of PDAC in the MASLD population (HR: 3.48; 95% CI: 2.69–4.50; P < 0.0001). Clinical cohorts confirmed the strong association between MASLD and hepatic metastases (OR: 7.06; 95% CI: 4.62–10.78; P < 0.0001). Experimental mouse models demonstrated that MASLD enhances tumor cell stemness, immune evasion, and focal adhesion in metastatic liver tissues. Mechanistically, MASLD-induced MIF secretion promotes CD44-positive PDAC cell migration, stemness, and adhesion. Targeting MIF, either genetically or pharmacologically using the MIF tautomerase inhibitor IPG1576 significantly attenuated liver metastasis in preclinical models. Validation in patient samples revealed elevated hepatic MIF and CD44 expression in MASLD-associated PDAC liver metastases. This study highlights the MIF-CD44 axis as a promising therapeutic target and underscores the importance of tailoring treatments for PDAC patients with concurrent MASLD.

Acute kidney injury (AKI) represents a formidable global health challenge characterized by high morbidity and mortality, yet effective pharmacological interventions remain elusive. Programmed cell death (PCD) pathways, orchestrating the depletion of renal tubular epithelial cells, are increasingly recognized as central drivers of AKI pathogenesis. Despite the rapid expansion of PCD-targeted agents in other therapeutic areas, their translational potential in AKI has not been fully exploited. This review provides a systematic synthesis of the molecular mechanisms governing diverse PCD modalities in renal injury, including apoptosis, pyroptosis, necroptosis, ferroptosis, cuproptosis, cellular senescence, and PANoptosis. We comprehensively analyze the intricate regulatory networks of these pathways and highlight emerging therapeutic targets, including transmembrane protein 16A (TMEM16A), signal transducer and activator of transcription 3 (STAT3), glutathione peroxidase 4 (GPX4), and others. Furthermore, we evaluate the developmental status of promising investigational agents, ranging from small-molecule inhibitors and agonists to novel PROteolysis-TArgeting Chimera (PROTAC) degraders (e.g., targeting STAT3). By integrating recent mechanistic advances with preclinical pharmacological evidence, this review outlines a rational framework for developing precision therapeutics targeting PCD signaling nodes, paving the way for novel strategies to halt AKI progression and facilitate renal recovery.

Effective therapy for relapsed or refractory central nervous system lymphoma (r/r CNSL) remains an unmet medical need. Meanwhile, developing antitumor drugs for CNS malignancies faces the dual challenge of achieving effective blood‒brain barrier (BBB) penetration and potent tumor cell killing. To address these challenges, a comprehensive predictive system was established to support decision-making during the discovery of HZ-A-018, a potent and BBB-permeable Bruton tyrosine kinase (BTK) inhibitor. This study further presents key preclinical results for HZ-A-018, as well as efficacy/safety data from a multicenter Phase 1 trial in r/r CNSL patients. HZ-A-018 demonstrated manageable safety, with only 19.2% of patients experienced grade 3 or higher adverse events according to the Common Terminology Criteria for Adverse Events version 5.0. Treatment with HZ-A-018 at the recommended phase II dose (RP2D) of 600 mg achieved an overall response rate (ORR) of 72.7% (95% CI, 39.0–94.0) and a 12-month survival rate of 90.5%. The Center for Drug Evaluation in China has authorized the initiation of this single-arm Phase II study as a pivotal registrational clinical trial for accelerated approval of HZ-A-018 for monotherapy in patients with r/r PCNSL. This trial has been registered under the identifiers ChiCTR2400091821 at www.chictr.org.cn and CTR20210181 at www.chinadrugtrials.org.cn.

OBJECTIVE:To investigate whether sonocavitation, induced by low-intensity focused ultrasound combined with microbubbles, can overcome paclitaxel resistance in ovarian cancer by promoting apoptosis through reactive oxygen species (ROS)-mediated mitochondrial dysfunction. METHODS:Paclitaxel-resistant ovarian cancer tissues and cell lines were compared with chemotherapy-sensitive counterparts for the expression of apoptosis-related proteins. Sonocavitation treatment was applied to resistant cells using optimized ultrasound parameters. Apoptosis, ROS production, mitochondrial morphology, oxygen consumption, mitochondrial membrane potential and mitochondrial membrane proteins were evaluated by flow cytometry, transmission electron microscopy, oxygen consumption assays, adenosine triphosphate (ATP) measurements, mitochondrial membrane potential assay kit staining and Western blotting. In vivo antitumor efficacy and biosafety were examined in paclitaxel-resistant xenograft mouse models, with tumor growth curves, survival analysis, and hematological/organ histology assessments. RESULTS:Paclitaxel-resistant ovarian cancer tissues exhibited elevated Bcl-2 and reduced Bax and Caspase-3, indicating impaired intrinsic apoptosis. Sonocavitation significantly increased apoptosis in resistant ovarian cancer cells and induced marked mitochondrial dysfunction, including reduced mitochondrial size, disrupted oxygen consumption, decreased ATP levels, collapse of mitochondrial membrane potential and destruction of mitochondrial membrane proteins. Cytochrome c release and activation of cleaved Caspase-3 confirmed mitochondrial-dependent apoptosis. In vivo, sonocavitation suppressed tumor growth and prolonged survival without causing systemic toxicity. ROS scavengers partially reversed these effects, confirming that ROS accumulation is a key mediator of the therapeutic mechanism. CONCLUSION:Sonocavitation induces apoptosis in paclitaxel-resistant ovarian cancer through ROS-mediated mitochondrial dysfunction and demonstrates effective tumor-suppressive activity with a favorable safety profile. These findings support sonocavitation as a promising adjuvant strategy to overcome chemoresistance and enhance ovarian cancer treatment outcomes.

The cannabinoid receptor 1 (CB1) has emerged as a promising candidate for next-generation non-opioid therapies. However, the development of therapeutics targeting CB1 has been consistently hindered by significant adverse effects. Here, through structure-activity relationship analyses focused on biased signaling, we rationally design two Gi-biased CB1 agonists, LZD503 and LZD505. Our design strategy employed structural spatial tuning of the agonist scaffold to disrupt specific molecular interactions and minimize steric conflicts with critical tip residues within the ligand-binding pocket, thereby promoting preferential Gi-pathway signaling. Cryo-electron microscopy structures of the CB1-G-protein complexes bound to these designed agonists confirmed that their anticipated conformational poses favored Gi-biased signaling. Both designed compounds demonstrated promising results by alleviating pain and mitigating unwanted responses in mice. The elucidated CB1 complex structures and the resulting insights establish a comprehensive framework for the structure-guided development of innovative CB1-targeted analgesics with reduced adverse effect profiles.

Pyroptosis, a lytic and pro-inflammatory form of programmed cell death executed by gasdermin (GSDM) family proteins through plasma membrane pore formation, represents a double-edged sword in cancer therapy. Initially distinguished from apoptosis and necrosis by its dependence on inflammatory caspases and inflammasome activation, pyroptosis is now understood to be fundamentally driven by the N-terminal fragments of cleaved GSDMs, which oligomerize to form cytotoxic pores. In cancer, pyroptosis induction exerts potent anti-tumor effects by directly eliminating malignant cells and stimulating immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) that recruit and activate immune cells, thereby synergizing with immune checkpoint blockade. Key strategies to induce tumor pyroptosis include chemotherapy, targeted agents, engineered bispecific antibodies, innovative nanoplatforms delivering bioactive N-terminal domains of GSDMs or pyroptosis inducers, and specific natural compounds. However, this therapeutic potential is counterbalanced by significant challenges: constitutive GSDM expression in normal tissues underlies severe chemotherapy toxicity; chronic pyroptosis in hypoxic tumor cores promotes immunosuppressive necrosis and metastasis; and non-lytic functions of GSDM can suppress anti-tumor immunity. Furthermore, cancer cells evade pyroptosis through epigenetic silencing, alternative splicing generating dominant-negative isoforms, and ubiquitin-mediated degradation of GSDMs. Harnessing the anti-tumor potential of pyroptosis while circumventing its detrimental roles requires precise targeting strategies, leveraging biomarkers for patient stratification, and understanding context-dependent outcomes.

A machine learning-guided strategy, which integrated unsupervised structural clustering to identify diverse scaffolds for molecular hybridization followed by synergistic QSAR and molecular docking screening, identified lead compound 7. Guided by this lead, a series of thieno[2,3-d]pyrimidine derivatives were developed as menin inhibitors through several rounds of rational structural optimization. Among them, compound A13 exhibited potent anti-proliferative activity against MV4-11 cells (0.379 ± 0.182 μM). Besides, mechanistic studies confirmed A13 disrupts menin-MLL interactions, induces cell differentiation, and selectively inhibits MLL-rearranged (MV4-11, MOLM-13) and DNMT3A/NPM1-mutated (OCI-AML3) leukemia cells. The stable binding mode of A13 with menin was further elucidated by molecular dynamics simulations. Moreover, A13 exhibited favorable oral pharmacokinetic properties, characterized by rapid absorption (Tmax = 1.67 h) and high plasma exposure (AUC0-t = 2241 ng h/mL), demonstrating its potential as a promising candidate for further preclinical development against MLL-rearranged AML.

Aptamer-drug conjugates (ApDCs) represent innovative therapeutics in recent drug development, emerging as a new modality for precision delivery. As a novel targeted cancer therapy strategy, ApDCs have significant advantages over antibody-drug conjugates (ADCs), including smaller molecular weight, higher chemical stability, lower immunogenicity, stronger tissue penetration, and easier engineering. Currently, ApDCs have established themselves as a highly competitive research landscape, garnering considerable attention from scientists worldwide. This review focuses on the latest progress in the ApDCs field from 2023 to 2025, with an emphasis on discussing solutions and emerging strategies to overcome the aforementioned challenges, aiming to provide references for promoting the further development and clinical application of ApDCs.