Triptolide, a bioactive diterpenoid epoxide isolated from Tripterygium wilfordii Hook. F. (Thunder God Vine), is a potent multi-target natural compound with significant anticancer potential. This systematic review with narrative synthesis evaluates preclinical evidence published between 2015 and 2026 on its molecular mechanisms, cancer-specific responses, and translational prospects, introducing a confidence-based framework to grade the strength of reported mechanisms. Across 51 studies, triptolide showed broad-spectrum anticancer activity in breast, lung, colorectal, pancreatic, hepatocellular, ovarian, prostate, glioma, and osteosarcoma models, acting mainly through mitochondrial apoptosis (92% of studies), reactive oxygen species generation, cell-cycle arrest, and modulation of NF-κB, PI3K/Akt/mTOR, STAT3, and Wnt/β-catenin signaling, with chemosensitization to cisplatin, gemcitabine, pemetrexed, and gefitinib reported in 31% of studies. Clinical translation, however, remains constrained by a therapeutic-index paradox: the same multi-target actions driving efficacy also underlie systemic toxicity, compounded by poor aqueous solubility, low bioavailability, and a narrow therapeutic window. The prodrug Minnelide has reached phase I/II trials, but substantial toxicity persists and no phase III data yet exist. Future progress will likely depend on improved delivery and toxicity-mitigation strategies rather than the discovery of additional molecular targets.

Immune checkpoint inhibitor (ICI)-associated transverse myelitis (TM) is a rare and severe neurological immune-related adverse event (n-irAE) with an incidence of < 0.01%, and the clinical management of steroid-unresponsive cases remains extremely challenging. This article reports the case of a 37-year-old male patient with biphasic pleural mesothelioma who developed ICI-associated TM after treatment with nivolumab combined with ipilimumab. Initial treatment with high-dose glucocorticoids plus intravenous immunoglobulin (IVIg) was ineffective. After mycophenolate mofetil (MMF) was added in combination with steroids for 1 month, the patient's neurological function showed slight improvement, and intramedullary contrast-enhanced signals on spinal MRI showed partial reduction. However, spinal cord cystic or myelomalacic changes suggested potentially irreversible parenchymal injury. Currently, the patient has restarted pemetrexed combined with carboplatin chemotherapy, and the disease status is stable. Based on recently published case series, case reports, and systematic reviews, this article discusses the second-line treatment strategies for steroid-unresponsive ICI-associated TM, aiming to provide a reference for clinical practice in managing such rare cases.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have provided significant clinical benefit to patients with EGFR-mutant non-small cell lung cancer (NSCLC), but multiple concurrent genetic alterations may limit their efficacy. We report a case of advanced lung adenocarcinoma harboring concurrent EGFR exon 19 deletion, ERBB2 amplification, and ERBB2 p.S310F mutation. The patient experienced disease progression after multiple lines of therapy, including osimertinib-based treatment, pemetrexed/carboplatin plus ivonescimab, and nab-paclitaxel plus Endostar. Considering that primary ERBB2 genetic alterations might contribute to the limited benefit from EGFR-TKI-based therapy, the patient subsequently received trastuzumab rezetecan monotherapy. After four cycles of treatment, the patient achieved a partial response in pulmonary lesions and a complete response in intracranial metastases. This case indicates that trastuzumab rezetecan may be a promising treatment option for EGFR-mutant NSCLC with concurrent ERBB2 genetic alterations, even after failure of multiple lines of treatment.

Mesenchymal-epithelial transition factor (MET) amplification is an uncommon but important oncogenic driver in non-small cell lung cancer (NSCLC), and its coexistence with high programmed death-ligand 1 (PD-L1) expression creates a therapeutic dilemma over how to sequence MET-directed therapy and immune checkpoint inhibition. We report a 65-year-old man who presented with weight loss, hoarseness with left vocal cord palsy, and right supraclavicular lymphadenopathy, with metastatic disease in the lungs, lymph nodes, and bone (with hepatic and brain metastasis emerging later on therapy). Biopsy confirmed metastatic lung adenocarcinoma. Comprehensive genomic profiling (CGP) showed MET amplification (copy number gain of 8, an intermediate-level amplification), a TP53 mutation, and high PD-L1 expression (tumor proportion score (TPS) ~80% by 22C3 immunohistochemistry at diagnosis and a VENTANA SP142 tumor cell (TC) score of 90% at progression; the two assays are not directly comparable). Because the CGP and PD-L1 results returned only after treatment had started, first-line platinum-doublet chemotherapy (nab-paclitaxel/carboplatin) was given, with a mixed response and a new hepatic metastasis. Second-line atezolizumab plus pemetrexed/carboplatin produced a partial response, followed by brain metastases. Third-line off-label capmatinib, used despite the absence of a MET exon 14 skipping mutation, produced a marked systemic response following brain radiotherapy and subsequent capmatinib. The patient then developed hepatic dysfunction that, against a background of concurrent radiological liver progression, was of uncertain cause; capmatinib was reduced and stopped, and he died approximately 30 months after diagnosis from liver failure and sepsis. This case illustrates the difficulty of sequencing therapy when MET amplification and high PD-L1 expression coexist. Notably, a marked response to capmatinib occurred despite an intermediate MET copy number below the threshold usually associated with benefit. Any role for combined or sequential MET inhibition and immunotherapy remains a hypothesis requiring prospective study rather than a conclusion supported by this single case, and cross-assay PD-L1 results should be interpreted with caution.

Lung cancer remains a major cause of cancer-related mortality worldwide, with current treatments such as surgery, chemotherapy, and immunotherapy facing limitations, including severe side effects and high costs. Hyperthermia (H) has emerged as a promising strategy to enhance tumor sensitivity to treatments and reduce toxicity. This study investigates the effects of H in enhancing the anti-tumor efficacy of pemetrexed (PEM) and altering the expression profile of hsa-MiR-548c-3p (tumor suppressor) in the A549 cell line. A549 cells were cultured in DMEM medium and divided into four groups: Control, and treatment with H, PEM, and a combination of H and PEM. Subsequently, cell viability, apoptosis percentage, release rate of LDH, production of ROS, and the expression level of hsa-MiR-548c-3p, CASP 8 and 9, and TYMS genes were measured. Results revealed that the combination of H and PEM treatment had greater antitumor effects compared to the other groups. The combination of H and PEM significantly reduced cell viability, increased the percentage of apoptosis, LDH release, and ROS production, and upregulated hsa-MiR-548c-3p, CASP 8, and 9, while downregulating TYMS. The findings suggest that H enhances the chemotherapeutic efficacy of PEM by upregulating hsa-MiR-548c-3p expression and promoting apoptosis in lung cancer cells, making it a promising complementary approach for overcoming drug resistance.

The use of targeted therapies has improved outcomes in patients with resected epidermal growth factor receptor-mutated non-small cell lung cancer, but uncommon and persistent dermatologic toxicities remain poorly characterized. We report a 71-year-old woman with resected lung adenocarcinoma harboring an epidermal growth factor receptor exon 21 L858R mutation. Following right upper lobectomy and systematic mediastinal lymph node dissection, pathological staging was pT2aN1M0 (stage IIB). She received four cycles of adjuvant cisplatin plus pemetrexed followed by planned three-year adjuvant Osimertinib. During Osimertinib treatment, she developed a persistent violaceous rash accompanied by progressive cutaneous hyperpigmentation. Osimertinib was temporarily interrupted, and dermatologic evaluation was performed, resulting in partial clinical improvement. Hyperpigmentation, however, persisted during follow-up. Other adverse events included grade 1 diarrhea, transient arthralgia, anorexia, and weight loss. Osimertinib was subsequently resumed and maintained. Nearly two years after surgery, the patient remains free of disease recurrence, with stable pigmentary skin changes. This case highlights an uncommon and prolonged dermatologic manifestation associated with Osimertinib and emphasizes the importance of recognizing atypical cutaneous toxicity to facilitate appropriate management and to facilitate appropriate dermatologic evaluation and individualized management of treatment-related toxicity.

Herein, we report a systematic ML-embedded virtual screening strategy for the repurposing of antifolates (hTS inhibitors) targeting Histone Lysine Methyltransferase (G9a/EHMT2), with experimental validation. Three pharmacophore models (3D QSAR, Common Feature, and Interaction), derived from known G9a inhibitors, were used in a database mining of the 1120 hTS inhibitors from the ChEMBL database. Candidates were filtered using a multi-tier screening strategy based on fit values, drug-likeness, ADMET, and TOPKAT criteria, followed by molecular docking to assess interactions with G9a's active site, including compounds such as UNC0642 and Raltitrexed as references. The top candidates were selected for strong docking scores, the ability to form at least three hydrogen bonds, and interaction with the lysine-binding tunnel. Among these, Pemetrexed exhibited a binding mode similar to Raltitrexed, forming critical hydrogen bonds and pi interactions with residues Leu1086, Ser1084, Tyr1154, Arg1157, and Phe1158, indicating its potential as a G9a inhibitor. Further analyses of RMSD, RMSF, ROG, and protein-ligand interactions confirmed the stability of Pemetrexed, and MM-GBSA binding energy calculations, along with residue-wise decomposition analysis, supported its strong affinity for G9a. An in vitro assay of Pemetrexed revealed G9a inhibitory activity with an IC50 of 304.90 nM, demonstrating its potency. Additionally, Pemetrexed exhibits lower activity against the G9a-like methyltransferase GLP than the references, confirming the compound's preferential activity for G9a over GLP. Furthermore, Pemetrexed improves the locomotor deficits associated with Aβ expression in C. elegans CL2006 worms in a dose-dependent manner, showing its potential as an epigenetic therapeutic for Alzheimer's Disease.

The phase III ADVANCE study prospectively assessed a chemotherapy-free strategy combining aumolertinib with definitive radiotherapy (RT) in patients with unresectable stage III non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations (ChiCTR.org: ChiCTR2000040590). Participants were assigned in a 1:1 ratio to either the experimental arm (110 mg daily aulomertinib plus RT) or the control arm (cisplatin/pemetrexed with RT). The primary endpoint was progression-free survival (PFS). Planned enrollment was 98 patients to detect a hazard ratio (HR) of 0.5. A protocol-prespecified real-world cohort (n = 125) was used for validation. 43 eligible patients were randomized (24 experimental, 19 control). The trial was terminated early following the prespecified interim analysis because of loss of equipoise in an open-label setting, slow accrual, and a large observed PFS difference. At a median follow-up of 25.5 months, the experimental arm had significantly longer PFS (median 34.0 vs. 7.4 months; HR 0.15; P < 0.001). Median overall survival (OS) was not reached vs. 30.5 months (HR = 0.32; P = 0.09). Neutropenia and nausea were more frequent in the control arm; quality of life favored the experimental arm. These findings were supported by real-world validation (n = 125, median follow-up 32.7 months), in which EGFR tyrosine kinase inhibitors (TKIs) + RT and TKIs+cCRT showed similar outcomes, both superior to cCRT (P < 0.001) (ClinicalTrials.gov: NCT04304638). The ADVANCE trial establishes a novel chemo-free strategy incorporating TKI and RT, which prolongs PFS and demonstrates promising OS in unresectable stage III EGFR-mutant NSCLC versus cCRT.

We report the case of a 77-year-old man with no known history of asbestos exposure who presented with a right-sided hydrocele. Histopathological analysis following hydrocele repair identified epithelioid-type malignant mesothelioma of the tunica vaginalis testis. Staging investigations confirmed disease confined to the hemiscrotum, and definitive management included right inguinal orchidectomy, excision of the spermatic cord to the deep inguinal ring, and wide local excision of the involved scrotal tissue. Initial surveillance imaging showed no recurrence, but nodal metastatic disease subsequently developed. The patient received first-line immunotherapy with ipilimumab and nivolumab but experienced progressive nodal disease. Second-line carboplatin-pemetrexed chemotherapy resulted in a mixed radiological response after three cycles, with para-aortic nodal oligoprogression managed using palliative radiotherapy. Following palliative radiotherapy and three further cycles of carboplatin-pemetrexed chemotherapy, imaging demonstrated a partial radiological response. Further surveillance revealed thoracic and intra-abdominal nodal progression, which was managed with a second course of palliative radiotherapy and was followed by renewed disease stabilisation. Subsequent progression involved pulmonary and intra-abdominal nodal disease, prompting initiation of third-line oral vinorelbine. Imaging demonstrated predominantly stable disease with isolated para-aortic oligoprogression, which was treated with a third course of palliative radiotherapy, after which vinorelbine was resumed. Approximately four years after diagnosis, the patient remained clinically stable, with an Eastern Cooperative Oncology Group (ECOG) performance status of 1, and was awaiting interval imaging to assess radiological disease status. This case illustrates that an individualised sequential treatment strategy incorporating immunotherapy, chemotherapy, and palliative radiotherapy to sites of oligoprogression may be associated with periods of disease control in metastatic malignant mesothelioma of the tunica vaginalis testis.

BRCA1 is a multifunctional tumor suppressor that orchestrates homologous recombination repair, chromatin remodeling, cell cycle control and apoptosis. Although pathogenic BRCA1 mutations are relatively uncommon, decreased BRCA1 protein expression, which is typically driven by accelerated proteasomal degradation, is implicated in aggressive breast cancer (BC), particularly triple‑negative (TN)BC. These mutations may modulate therapeutic response to DNA‑damaging agents. Given the absence of clinically available strategies to restore BRCA1 stability, the present study evaluated whether pemetrexed (Peme), a multitargeted antifolate identified through an in silico US Food and Drug Administration‑approved drug screen, modulates BRCA1 protein homeostasis in TNBC models. BRCA1 protein abundance, ubiquitination and turnover were assessed using immunoblotting, ubiquitin pull‑down and cycloheximide chase analyses and BRCA1 domain mutants. Functional consequences of Peme treatment were measured by apoptosis assay and BRCA1‑dependent signaling readouts. The radiosensitizing effect of Peme was evaluated in vitro and validated in TNBC xenografts. Peme increased BRCA1 protein levels without altering BRCA1 mRNA, indicating post‑translational regulation. Mechanistically, in silico docking and BRCA1 deletion mutant analyses suggested that the BRCA1 C‑terminal domain may contribute to the effect of Peme on BRCA1 stability, suppressing ubiquitin‑mediated proteasomal degradation and resulting in protein stabilization. Stabilized BRCA1 enhanced apoptotic responses, whereas BRCA1 knockdown attenuated these effects. Combined Peme‑radiation treatment significantly potentiated cytotoxicity in vitro and inhibited tumor growth in vivo, demonstrating a radiosensitizing effect linked to BRCA1 stabilization. Collectively, these findings identified Peme as a BRCA1‑stabilizing agent that enhances therapeutic response to radiation in TNBC. Pharmacological restoration of BRCA1 stability represents a promising strategy to overcome therapeutic resistance in BRCA1‑deficient or functionally compromised BC.

Boolean networks are powerful frameworks for capturing the logic of gene-regulatory circuits, yet their combinatorial explosion hampers exhaustive analyses. Here, we present a systematic reduction of a published 31-node Boolean model that describes cisplatin- and pemetrexed-resistance in non-small-cell lung cancer to a compact 9-node core that exactly reproduces the original attractor landscape. Through a sequence of biologically guided reductions (31→29→14→9 nodes), the streamlined network shrinks the state space by four orders of magnitude, enabling rapid exploration of critical control points, rules fitting, and candidate therapeutic targets. Extensive synchronous and asynchronous simulations, combined with a Boolean rule-fitting algorithm that removes spurious limit cycles, confirm that the three clinically relevant steady states and their basins of attraction are conserved and reflect resistance frequencies close to those reported in clinical studies. The reduced model provides an accessible scaffold for future mechanistic and drug-discovery studies.