Immune checkpoint inhibitors (ICIs) targeting PD-1 are effective cancer therapies but can cause severe myocarditis. The molecular mechanisms linking PD-1 blockade to cardiomyocyte damage are incompletely understood. We established a murine model of anti-PD-1-associated cardiac injury and used human AC16 cardiomyocytes in co-culture with CD8+ T cells. Global Fundc1 knockout (Fundc1-/-) mice and cardiac-specific Fundc1 reconstitution via AAV9 were employed to investigate the role of this mitophagy receptor. Cardiac function was assessed by echocardiography, and injury was evaluated through serum biomarkers, histology, and molecular analyses. Anti-PD-1 treatment induced cardiac dysfunction, myocardial T-cell infiltration, and reduced myocardial FUNDC1 expression in mice. FUNDC1 deficiency, both in vitro and in vivo, aggravated anti-PD-1-associated cardiomyocyte injury, cardiac dysfunction, inflammation, and fibrosis. Conversely, FUNDC1 overexpression or cardiac-specific Fundc1 restoration attenuated these pathological changes. Mechanistically, FUNDC1 loss was associated with altered mitophagy-related marker profiles, mitochondrial protein accumulation, increased oxidative stress, and mitochondrial functional impairment. FUNDC1-mediated mitochondrial quality control may represent an endogenous protective mechanism against anti-PD-1 antibody-associated cardiac injury.

Oxaliplatin resistance remains a major obstacle in the treatment of colorectal cancer (CRC). This study aimed to determine whether MYC contributes to oxaliplatin resistance by regulating ferroptosis and to clarify the downstream mechanisms involving FTH1 and GPX4.

Olaparib has demonstrated clinical benefit in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA pathogenic or likely pathogenic variants (PVs) in randomized clinical trials; however, multicenter real-world data in Japanese patients remain limited.

The preservation of the tumor immune microenvironment (TIME) ex vivo is essential for investigating tumor-immune interactions and developing effective immunotherapies. However, current culture models often fail to maintain autologous immune cells or support high-throughput testing. To overcome these limitations, we establish and validate a novel miniaturized-tumor culture (MTC) platform.

Doxorubicin (DOX) is a potent chemotherapeutic agent whose antitumor benefits are limited by a well-recognized, dose-dependent cardiotoxicity. While previous studies have implicated inflammatory pathways in DOX-induced cardiomyopathy (DIC), the role of CCR2 in this process remains incompletely defined. This study aims to investigate whether CCR2 deficiency confers cardioprotection against DIC and to uncover the molecular mechanisms involved.

The combination therapies are significantly more effective than monotherapies in enhancing anticancer efficacy, reducing drug-related toxicity, and lowering the risk of drug resistance in cancer treatment. However, achieving precise delivery of the drugs to the tumor site remains a major challenge. With the deepening exploration of surface-engineered nanocarriers, ligand-modified liposomal drug delivery systems (LLDDS) are constructed by integrating the active-targeting properties of functional ligands (such as peptides, glycans, and aptamers) with the inherent advantages of liposomes. LLDDS show promise for exhibiting strong tumor-targeting capability, improving pharmacokinetics, biodistribution, and therapeutic efficacy of anticancer agents, such as chemotherapy drugs, and enabling the multifunctional integration of multiple therapeutic strategies. This review summarizes the development of liposomes and ligand-mediated surface modification strategies. More significantly, the development of multifunctional liposomes, targeted delivery, improved anticancer effectiveness, and possible anticancer mechanisms are highlighted in the discussion of LLDDS's recent advancements for integrated therapy approaches in a variety of malignancies. Lastly, the potential and difficulties of clinical translation in this ever-evolving area are examined.

Triple negative breast cancer (TNBC) and ovarian cancer share many molecular features and are primarily treated with surgical resection and aggressive chemotherapy regimens. Unfortunately, survival rates for patients with advanced metastatic disease are poor, highlighting the need for innovative therapeutic approaches.

Pathological ocular neovascularization is a major driver of vision-threatening retinal diseases. This study aimed to investigate the role and therapeutic potential of miR-15a-5p in ocular neovascular disorders.

Immune checkpoint inhibitors (ICIs) have revolutionized lymphoma treatment, yet resistance driven by complex regulatory networks remains a major hurdle. Circular RNAs (circRNAs) have emerged as central signaling hubs that integrate metabolic, inflammatory, and oncogenic cues to fine-tune immune checkpoints such as PD-L1 and CD47 in lymphoma. Here, we systematically dissect the molecular mechanisms by which circRNAs govern immune checkpoints in lymphoma, including nuclear transcriptional control, interactions with RNA-binding proteins (RBPs), competitive endogenous RNA (ceRNA) networks, and micropeptide translation. We differentiate between cell-extrinsic, exosome-mediated reprogramming of the tumor microenvironment and cell-intrinsic circRNA circuits within lymphoma cells spatially. Subtype-specific investigations demonstrate the importance of Epstein-Barr virus (EBV)-encoded circRNAs in immune evasion and the synergistic interactions between 9p24.1 amplification and circRNAs in classical Hodgkin lymphoma (cHL). While therapeutic approaches including antisense oligonucleotides, CRISPR-Cas13, and nanodelivery technologies demonstrate preclinical synergy with ICIs, circulating circRNAs show potential as dynamic indicators for predicting ICI responses. We also critically examine ongoing discussions about the flaws of current model systems, the technological constraints of current validation techniques, and the physiological significance of the ceRNA hypothesis. Positioning circRNAs as multimodal regulatory hubs, this review provides a theoretical framework for developing circRNA-based immunotherapies to overcome resistance in lymphoma.

Nucleolar Protein 14 (NOP14), a highly conserved factor in eukaryotes, is essential for pre-18S rRNA processing and small ribosomal subunit assembly. Emerging evidence underscores its pivotal regulatory role in the progression of various malignancies. Nevertheless, its functional involvement in Diffuse large B-cell lymphoma (DLBCL), particularly its capacity to modulate the tumor immune microenvironment, remains to be fully elucidated.

Mitotane remains the cornerstone of adrenocortical carcinoma. However, its real-world safety profile is poorly defined. This study systemically evaluated mitotane-associated adverse events (AEs) and characterized multivariable patterns of serious outcomes using a combined pharmacovigilance and machine learning approach.

Spatiotemporal control over supramolecular assemblies holds promise for precise theranostics, yet conventional designs often require an extensive modification of the backbone by introducing responsive motifs. Herein, with minimal interference of the molecular backbone, we report a chiral engineering strategy to enhance the pH sensitivity of a tripeptide-drug conjugate (PDC). Specifically, homochiral PDC forms supramolecular nanofibers with a low pH dependence, whereas the heterochiral isomer with alternating D/L residues exhibits a highly pH-dependent self-assembly. Importantly, in carbonic anhydrase IX (CAIX)-overexpressing tumor cells, fibrous assemblies of homochiral PDCs occur at the cell surface, while heterochiral PDCs form nanofibers within lysosomes via protonation. This process subsequently promoted lysosomal membrane permeabilization and enhanced CAIX inhibition, which turns into an efficient way of enhancing cellular Fenton reactions to evoke ferroptosis, thereby improving the antitumor efficacy in breast tumors. Overall, this work proposes a chiral engineering approach for enhancing the pH sensitivity of supramolecular assemblies, which establishes an efficient strategy for spatiotemporal control over supramolecular assemblies and offers alternative insights into the biological effects of heterochirality.

Glioblastoma (GB) is the most aggressive primary malignant brain tumor in adults and remains associated with poor survival despite surgical resection followed by radiotherapy and temozolomide (TMZ) chemotherapy. Intrinsic and acquired resistance to TMZ, including MGMT-dependent DNA repair and activation of pro-survival pathways, could decrease treatment efficacy. Drug repurposing offers an attractive strategy to identify agents that may enhance TMZ activity because these drugs already have known pharmacokinetic and safety profiles. This narrative review summarizes the available evidence on repurposed drugs investigated as potential modulators of TMZ response in GB.

The expanding clinical use of Antibody-Drug Conjugates (ADCs) necessitates a clearer understanding of their real-world toxicity profiles across diverse clinical settings. This retrospective pharmacovigilance study analyzed 19,697 adverse event (AE) reports for seven approved ADCs from the FDA Adverse Event Reporting System (FAERS) database (Q1 2004 to Q1 2025). Using disproportionality analysis validated by multivariable logistic regression, we identified safety signals for both monotherapy and combination regimens. The analysis revealed that toxicity profiles are strongly driven by an ADC's molecular structure and treatment setting. Target-specific 'on-target, off-tumor' effects were prominent, linking Nectin cell adhesion molecule 4 (NECTIN-4) targeting to skin reactions, Trophoblast cell-surface antigen 2 (TROP2) to gastrointestinal toxicities, and both folate receptor α (FRα) and tissue factor (TF) to ocular disorders. Furthermore, payload and linker types drove distinct toxicities; topoisomerase I inhibitors were associated with increased respiratory toxicity and mortality, while non-cleavable linkers conferred a significantly stronger risk of hepatobiliary toxicity. Combination regimens not only amplified specific risks, such as endocrine disorders with immune checkpoint inhibitors (ICIs), but also fundamentally reshaped toxicity kinetics, accelerating AE onset with ICIs while significantly delaying it with other combinations. This real-world analysis confirms that ADC toxicities are highly specific to their molecular design and clinical context, highlighting that understanding these complex structural and kinetic interplays is essential for optimizing safety management in clinical practice.

Prostate cancer (PCa) is one of the most common cancers in males, and its treatment remains challenging due to the tumor microenvironment (TME) with immunosuppressive properties and limited response to anti-PD-1 therapy. Gut microbiota-derived metabolites have recently emerged as modulators of cancer immunometabolism, however, their role in PCa progression and immunotherapy is poorly understood. Here we found that indole-3-lactic acid (ILA), a metabolite produced by Lactobacillus plantarum, exerted dual anti-tumor effects on PCa cells and the TME. Mechanistically, ILA activates the aryl hydrocarbon receptor (AHR), and the resulting AHR/ARNT heterodimer translocates into the nucleus and binds to the promoter of ASF1B. This heterodimer then recruits the HDAC1/2-NuRD complex to reduce H3K27ac levels and suppress ASF1B expression. ASF1B binds to specific residues of ENO1 via its N-terminal core domain and enhances ENO1 enzymatic activity. ILA-induced downregulation of ASF1B impairs this interaction, reduces ENO1 activity, and suppresses the PI3K/Akt pathway, thereby inhibiting the malignant phenotypes of PCa cells. Concurrently, ILA decreased CXCL8 secretion by inhibiting the PI3K/Akt/NF-κB pathway, enhancing CD8+ T cell infiltration and M1 macrophage polarization, thereby remodeling the TME. Additionally, ILA synergized with anti-PD-1 therapy to more effectively suppress tumor growth. These findings reveal a novel mechanism by which gut microbiota-derived metabolites regulate PCa progression and immunometabolism, positioning ILA as a potential therapeutic agent to improve PCa treatment.

An encrusting, algae-associated octocoral, Briareum stechei, afforded three 8,17-epoxybriarane diterpenoids, including the known compound briaexcavatolide B (1) and two previously undescribed analogues, briastecholides Q (2) and R (3). The absolute configuration of 1 was established for the first time by single-crystal X-ray diffraction analysis. The planar structures and relative configurations of 2 and 3 were determined through extensive spectroscopic analyses. In bioactivity evaluation, compound 2 exhibited cytotoxic effects toward the human acute lymphoblastic leukemia cell lines Molt-4 and CCRF-CEM.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and is often diagnosed at an intermediate stage in patients with chronic liver disease. Transarterial chemoembolization (TACE) is the first-line treatment in this setting. However, drug response remains variable and optimal chemotherapeutic selection unresolved. Idarubicin (IDA) has previously demonstrated antitumor activity comparable to doxorubicin (DOX), with improved emulsion stability and membrane permeability. 3D patient-derived organoids (PDOs) have also recently emerged as physiologically relevant systems that recapitulate tumor characteristics and inter-patient heterogeneity more accurately than conventional 2D cell cultures. In this study, we characterized HCC PDOs and investigated their utility as an ex vivo model to assess therapeutic responses. We generated organoids from tumor and non-tumor liver biopsies collected from HCC patients prior to TACE-treatment. PDOs partially preserved tumor architecture and phenotypic features. IDA exposure resulted in a concentration-dependent reduction in organoid growth, with marked inter-patient variability in drug response. Comparative analyses showed that IDA was more potent than DOX, with lower IC₅₀ values across all patient-derived samples. IDA also induced transcriptional changes associated with cellular stress, inflammation, and proliferation pathways. However, ex vivo drug‑sensitivity testing in PDOs did not correlate with clinical response to TACE. These findings confirm the feasibility of generating HCC PDOs and using them to evaluate differential sensitivity to TACE‑associated chemotherapeutic agents ex vivo, although their ability to predict clinical efficacy remains unproven. While IDA exhibited greater cytotoxic activity than DOX in organoid cultures, this observation was based on in vitro sensitivity assays and does not establish clinical superiority. Furthermore, the absence of correlation between PDO drug sensitivity and clinical TACE response indicates that PDO-based prediction of treatment outcome remains challenging in this setting.

Chalcones (1,3-diphenyl-2-propen-1-one) are open-chain flavonoids recognized for their structural diversity and broad pharmacological activities. Electrophilic α,β-unsaturated carbonyl systems and versatile substitution patterns on aromatic rings have positioned the chalcones as privileged structures in medicinal chemistry. This review highlights the contributions of Brazilian investigations to the advances of chemistry and bioactivity of natural and synthetic chalcones over the last 40 years. A systematic search of PubMed, Scopus, Embase, and Web of Science up to February 2026 identified 661 publications, revealing a growing interest since the early 2000s and reflecting the consolidation of chalcone as a central subject of research groups. Brazilian investigations have shown chalcones as antibacterial, antifungal, antiparasitic, anticancer, and anti-inflammatory agents, affording pivotal insights into structure-activity relationships and mechanisms of action at the molecular level. In addition, we submitted the most active chalcones to in silico evaluations, using SwissADME web tool, allowing a comparative analysis of their physicochemical, pharmacokinetics, and drug-likeness properties. The results indicated the majority of these compounds demonstrated an appropriate drug-like behavior. Collectively, the set of findings has positioned Brazil as an important research powerhouse of chemistry and pharmacology of chalcone and its derivatives, which may impact the discovery of innovative therapeutic agents.

Ultrasmall cyclodextrin-based nanogels (CDngs) crosslinked with ethylene glycol diglycidyl ether (EGDE) were tested as drug delivery systems for poorly water-soluble anticancer agents for the first time. Two compounds with well-established pharmacological activity but critical solubility limitations, i.e., Osthole and Combretastatin A-4 (CA-4), were selected to evaluate the encapsulation capacity and performance of the nanogel platform. After preliminary screening through experimental and docking investigation, CA-4 was chosen as the reference compound. Among the formulations developed, the CA-4/loaded nanogel displayed the highest encapsulation efficiency (EE%). Despite a less-than-ideal host-guest fit, the large cavity of γ-CD allows for efficient drug encapsulation and higher loading capacity. The optimized formulation was tested in vitro to assess both the biocompatibility of γ-CDngs, as well as the anticancer efficacy of CA-4 loaded γ-CD and γ-CDngs. We demonstrate that empty systems exhibit intrinsic biocompatibility, showing no cytotoxicity toward the A2780 cancer cell line under experimental conditions. Furthermore, the CA-4 loaded γ-CDngs retained and enhanced the cytotoxic properties of the free drug against this cell line, compared to the corresponding native γ-CD. Collectively, these findings validate CDngs as a promising and innovative platform for the delivery of hydrophobic anticancer molecules and support their potential for further therapeutic development.

Natural and synthetic protoflavonoids exhibit a wide range of anticancer activities, including strong antiproliferative, proapoptotic, and DNA damage response-inhibitory activities; however, the surrounding chemical space has remained largely unexplored. In this study, we report the synthesis and biological evaluation of a focused compound library containing the p-hydroxydienone pharmacophore of protoflavonoids. Eleven derivatives were synthesized and characterized from chalcone precursors, and their antiproliferative activity was evaluated in four human adherent gynecological cancer cell lines (MCF-7, MDA-MB-231, HeLa, and SiHa). The investigated compounds exhibited mild to strong activity, with several showing notable selectivity for triple-negative MDA-MB-231 cells. Our findings suggest that the unexplored chemical space around protoflavonoids might encompass compounds with valuable bioactivity and warrant further research.