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Early identification of breast cancer is essential for improving survival rates, yet current screening approaches often exhibit inadequate specificity or excessive invasiveness. Serum Raman spectroscopy (RS) provides a quick, non-destructive option, but its clinical use is impeded by the complexity of spectral data interpretation. Herein, we presented an interpretable deep learning framework, a one-dimensional convolutional neural network with a patient-voting strategy(PV-CNN), to evaluate serum RS from 732 individuals (366 patients and 366 healthy controls). Our model achieved a diagnostic accuracy of 95.21%, a sensitivity of 92.38%, and a specificity of 97.00%, significantly surpassing the performance of conventional ML algorithms. Furthermore, we employed Grad-CAM and SHAP analyses to elucidate the decision-making processes of deep learning, representing a significant advancement in addressing the "black-box" issue. This interpretability analysis found that tryptophan (1017 cm-1) and phenylalanine (1002 cm-1) were key Raman spectral indicators for breast cancer diagnosis. This study demonstrates that interpretable deep learning-enhanced RS can serve as a reliable, label-free, and physiologically explainable method for breast cancer detection.

Calcium ions (Ca2+) serve as a pivotal intracellular second messenger, participating in core physiological processes including cell proliferation, neurotransmission, and apoptosis. The maintenance of calcium homeostasis depends on the precise interplay of plasma membrane channels and intracellular organelle stores. Dysregulation of calcium signaling is implicated in the pathogenesis of multiple diseases, including Alzheimer's disease, cancer, and cardiovascular disorders. Conventional pharmacological interventions are limited by off-target effects, insufficient bioavailability, and a lack of temporal and spatial control. Ca2+-regulated nanoplatform achieves spatiotemporally controlled drug release and responsive calcium level modulation through advanced surface engineering and stimulus-responsive design, substantially improving therapeutic precision and efficacy. Furthermore, nanoprobes permit real-time monitoring of calcium dynamics with high sensitivity and resolution. This comprehensive review systematically summarizes and highlights significant advances in engineering versatile nanoplatforms for calcium homeostasis modulation, focusing on constructed nanocarriers for drug delivery, functional nano-regulators for calcium flux intervention, and sensitive nanoprobes for real-time calcium imaging and quantification. Current challenges and future directions are also discussed to inspire the development of next-generation nanotheranostic platforms for precise diagnosis and treatment of calcium homeostasis-related diseases.

The increasing prevalence of antibiotic-resistant Helicobacter pylori (R-H. pylori) poses a significant clinical challenge, contributing to persistent gastritis, peptic ulcers, and gastric cancer. Conventional antibiotic therapies are increasingly limited by resistance, incomplete eradication, and disruption of the gut microbiota. To address these challenges, we developed pH-responsive iron-doped ammonium citrate carbon dots (Fe-CDs), a nanozyme with intrinsic specificity for targeting and eradicating R-H. pylori within the acidic gastric microenvironment. Fe-CDs exhibit dual oxidase (OXD)- and peroxidase (POD)-like catalytic activities that are selectively activated under acidic conditions, driving the localized generation of reactive oxygen species (ROS) via Fenton and Fenton-like reactions involving Fe(II) and endogenous hydrogen peroxide (H₂O₂). The nanozyme shows strong binding affinity for H. pylori through ammonium (NH4+)-mediated interactions and specifically targets Urel, thereby inhibiting urease activity and disrupting bacterial acid resistance. This dual mechanism-acid-enhanced ROS production combined with urease suppression-confers potent bactericidal effects against R-H. pylori while preserving commensal microbiota and minimizing off-target damage. Transcriptomic analysis of infected gastric tissue revealed that Fe-CDs induce ROS-mediated stress pathways and metabolic disruption in H. pylori. In vivo studies confirmed that Fe-CDs significantly reduce bacterial load in R-H. pylori-infected mice with negligible toxicity. These findings highlight Fe-CDs as a targeted, antibiotic-free therapeutic strategy for resistant gastric infections and offer a promising alternative to conventional treatments.

Immunotherapy represents a pioneering approach in clinical cancer treatment, but its application is often limited by insufficient immune stimulation and off-target side effects. Therefore, developing novel nanomaterials capable of precisely reshaping the tumor microenvironment (TME) is crucial for enhancing the efficacy of tumor immunotherapy. Herein, we constructed a "precision immune bomb" DOX@MZIF-P3 embodying a "PD-L1-targeted, on-site unlocking, local detonation" strategy. It actively targets and blocks highly expressed programmed death ligand 1 (PD-L1) on tumor cells, achieving tumor accumulation while attenuating immune evasion. In response to the TME, it depletes glutathione (GSH) and releases effector substances including doxorubicin (DOX), Mn2+, and Zn2+. Specifically, DOX induces apoptosis via DNA damage and elevates intratumoral H₂O₂ levels. Mn2+ generates reactive oxygen species (ROS) through Fenton-like reactions to trigger ferroptosis, while simultaneously sensitizing and augmenting the stimulator of interferon genes (STING) pathway. Zn2+ overload induces tumor cell pyroptosis and further promotes immunogenic cell death (ICD). Additionally, synergy between activated STING pathway and ICD enhances immune cell infiltration in tumor tissue and increases the levels of related inflammatory factors in the TME, ultimately promoting immunotherapy. This strategy precisely activates tumor immunity while significantly reducing off-target toxicity, effectively inhibiting primary tumor growth and blocking metastasis, providing a new paradigm for precision tumor immunotherapy.

Targeting cancer stem cells (CSCs) has emerged as a promising strategy for cancer therapy and prevention. The human cytochrome P450 enzyme CYP4Z1 has been identified as a potential therapeutic target due to its role in promoting breast cancer stemness. Aiming to develop potent and selective CYP4Z1 inhibitors, our strategy involved systematic structure-activity relationship (SAR) studies of the lead compound XD-2 (1-benzyl-1H-imidazo [4,5-c] pyridine), which led to its structural optimization. A series of derivatives were designed and synthesized to enhance drug-like properties, inhibitory activity, and selectivity. Among all the synthesized compounds, the preferred analog C8, which features an imidazo[4,5-c]pyridine core connected to a terminal butyl group via an amide-containing linker, exhibited the most potent CYP4Z1 inhibitory activity, with an IC50 value of 55.3 nM against CYP4Z1. Molecular docking studies revealed that the introduced side chain extended into the hydrophobic subpocket and the phenyl group established additional aromatic stacking interactions with Trp120. Subsequent in vitro and in vivo biological assessments confirmed that compound C8 potently diminished stemness marker expression, impeded spheroid formation, and attenuated both metastatic potential and tumor-initiating capacity in breast cancer cells. Collectively, these results underscore the promise of C8 as a leading candidate for advancing clinically viable CYP4Z1-targeted therapies in breast cancer.

Depletion of the splicing factor RBM39 disrupts spliceosome function and induces widespread RNA splicing defects, leading to antiproliferative effects in susceptible cancer cells. Here, we report the discovery and characterization of a new series of biphenyl-containing RBM39 degraders. The lead compound 42 promotes RBM39 degradation through formation of a ternary complex with RBM39 and DCAF15/DDB1 in a Cullin-RING E3 ligase- and proteasome-dependent manner, consistent with a molecular glue mechanism. Transcriptomic analyses in HCT-116 and K562 cells revealed extensive alternative splicing alterations and suppression of cell-cycle-associated pathways, resulting in G2/M-phase arrest without apoptosis. Comparative cellular profiling identified 41 (YSA64) as a potent analog in acute myeloid leukemia MV4-11 cells and Ewing sarcoma A673 cells, disease contexts that have been minimally explored for RBM39 degraders. Notably, 41 exhibited favorable oral pharmacokinetics and significant antitumor efficacy in MV4-11 xenograft models. Collectively, this work expands the chemical space of RBM39 degraders and supports their continued development as RNA splicing-targeted anticancer agents.

The fibroblast growth factor receptors (FGFRs) have garnered considerable attention as promising therapeutic targets in oncology, given their pivotal involvement in regulating cell proliferation, differentiation, and various other physiological processes. In this study, we have designed and synthesized a series of FGFR inhibitors featuring the 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one scaffold as a core structural motif. Notably, among these derivatives, compound 1a emerged as a potent inhibitor of four distinct FGFR subtypes, demonstrating superior efficacy in suppressing the proliferation of Huh7 hepatocellular carcinoma cells compared to BGJ398, a clinically validated FGFR inhibitor. In preclinical evaluations, 1a exhibited remarkable pharmacokinetic properties (oral bioavailability = 66.9%). In Balb/c mice bearing Huh7 xenografts, 1a achieved a 90.5% tumor growth inhibition rate at a dose of 50 mg/kg, with no discernible signs of systemic toxicity. Collectively, these findings indicate that 1a holds great potential as a broad-spectrum FGFR inhibitor for cancer treatment, supporting its further development in clinical settings.

c-Met inhibitors have demonstrated encouraging efficacy in the treatment of non-small cell lung cancer. However, some of these drugs are conditionally approved and still face certain limitations and challenges, primarily manifested as poor blood-brain barrier penetration, off-target toxicity, drug resistance, and low oral bioavailability. These factors restrict their clinical efficacy and widespread application. To discover novel c-Met inhibitors with high potency, minimal toxic side effects, and the ability to penetrate the blood-brain barrier, we designed and synthesized 33 new pyrimidine derivatives using Tepotinib as the lead, employing bioisosterism and conformational restriction strategies. Their anti-tumor activities were evaluated in vitro and in vivo. Among these derivatives, the optimal compound 11g exhibited IC50 values of 4.01 nM and 3.50 nM against MHCC97H and EBC-1 cells, respectively. In the EBC-1 xenograft mouse model, at a dose of 4 mg/kg, 11g achieved a tumor growth inhibition (TGI) rate of 64.9%, which was significantly higher than that of Tepotinib (33.5%) at the same dose. Pathological evaluation further confirmed that 11g possessed improved safety and reduced toxic side effects. In addition, 11g displayed superior blood-brain barrier permeability and metabolic stability compared with the lead compound. Mechanistic studies demonstrated that 11g effectively inhibits tumor cell proliferation and migration by binding to the c-Met protein and induces cell apoptosis. In summary, as a novel and highly potent c-Met inhibitor, 11g shows promising potential for the treatment of NSCLC, particularly in the prevention and treatment of tumor brain metastasis.

Nur77, an orphan nuclear receptor, is involved in the development and progression of multiple tumors. In our previous study, we have shown that the protein level of Nur77 is elevated in colon tumors compared to adjacent normal tissues, highlighting its potential as a promising target for colorectal cancer therapy. Significantly, we have identified BI1071 as a Nur77-targeting compound that induces apoptosis in colorectal cancer cells. Based on the scaffold of BI1071, by substituting the indole group of BI1071 with a pyrrolyl group on one side, we rationally designed and synthesized a series of novel BI1071 analogues named SIM-C-PhCF3+Cl- targeting Nur77, and the structure-activity relationship of these BI1071 derivatives was summarized. From this series of compounds, A6 exhibited the strongest binding affinity to Nur77 (Kd = 0.40 ± 0.05 μM) and the most potent anti-proliferative activity against HCT116 and MC38 colorectal tumor cell lines, with IC50 values of 0.53 ± 0.06 μM and 0.16 ± 0.007 μM, respectively. Interestingly, unlike BI1071, which triggers Nur77-dependent apoptosis, compound A6 suppressed colon cancer cell proliferation predominantly by inducing Nur77-dependent mitotic arrest. Collectively, our findings provide a foundation for further investigation and development of Nur77-targeting antimitotic molecules toward colorectal cancer therapy.

The overexpression of the transcriptional enhanced associate domain (TEAD), which regulates gene transcription linked to cell growth, drives the proliferation in cases of hepatocellular carcinoma (HCC). In order to discover novel TEAD inhibitors that are more effective and have better efficacy and pharmacokinetic properties for treating HCC, this study employed a cyclization strategy to generate a novel indole-based scaffold of TEAD inhibitors. A comprehensive and systematic structure-activity relationship (SAR) analysis identified the most promising compound: LC-TD-05, a non-covalent, partial TEAD inhibitor with selective activity against TEAD1, TEAD2 and TEAD4, but reduced potency against TEAD3. LC-TD-05 exhibits good potency against TEAD1/2/4 (TEAD1 IC50 = 116.6 ± 21.7 nM, TEAD2 IC50 = 168.7 ± 17.1 nM, TEAD4 IC50 = 68.3 ± 18.2 nM), demonstrates favorable oral bioavailability (F = 53.7%), and exhibits significant anti-tumor activity in HCC LM3 models in vitro (LM3 cell IC50 = 248 ± 27.9 nM) and in vivo (TGI = 75%). Overall, this study provides a novel scaffold for TEAD inhibitors, enabling more effective interventions against HCC.