Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age‐Related Conditions in Mice

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 23, 2025

Cellular senescence is a cell fate triggered by stressful stimuli and displays hypersecretory feature, the senescence-associated secretory phenotype (SASP). Senescent burden increases with aging contributes to age-related organ dysfunction multiple chronic disorders. In this study, large scale screening of natural product library for senotherapeutic candidates performed. Apigenin, dietary flavonoid previously reported antioxidant anti-inflammatory activities, exhibits capacity targeting senescent cells as senomorphic agent. This compound blocks interactions between ATM/p38MAPK HSPA8, preventing transition an acute stress-associated (ASAP) toward SASP. Mechanistically, apigenin targets peroxiredoxin 6 (PRDX6), intracellular redox-active molecule, suppressing iPLA2 activity PRDX6 disrupting downstream reactions underlying SASP development. Apigenin reduces severity cancer malignancy promoted stromal in culture, while restraining chemoresistance when combined chemotherapy anticancer regimens. preclinical trials, improves physical function animals premature aging-like state, alleviating frailty cognitive impairment. Together, study demonstrates feasibility exploiting achieve geroprotective effects modulating SASP, thus providing baseline future exploration agents conditions.

Language: Английский

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Comprehensive analysis based on IFN-γ and SASP related genes, bulk RNA and single-cell sequencing to evaluate the prognosis and immune landscape of stomach adenocarcinoma

Genes & Genomics, Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

Language: Английский

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Targeting the Senescent Tumor Microenvironment to Sensitize Immunotherapy

Highlights in Science Engineering and Technology, Journal Year: 2025, Volume and Issue: 139, P. 260 - 271

Published: April 28, 2025

The tumor microenvironment (TME) plays a pivotal role in cancer progression, metastasis, and therapeutic resistance. Cellular senescence within the TME, characterized by irreversible growth arrest senescence-associated secretory phenotype (SASP), profoundly impacts biology immunotherapy efficacy. senescent TME promotes growth, invasion, metastasis through complex interactions between cells, SASP factors, extracellular matrix (ECM). Simultaneously, senescence-induced alterations immune cell function, including T exhaustion, macrophage polarization, impaired natural killer (NK) cytotoxicity, contribute to an immunosuppressive niche that hinders immunosurveillance fosters evasion. Mounting evidence suggests is critical mediator of resistance checkpoint inhibitors (ICIs). Senescence-associated changes dampen antitumor immunity reducing CD8+ infiltration functionality while promoting accumulation populations such as regulatory cells (Tregs) myeloid-derived suppressor (MDSCs). Consequently, strategies targeting have emerged promising approaches enhance ICI Senolytic agents, inhibitors, combinatorial therapies aimed at eliminating modulating SASP, reprogramming shown potential preclinical models sensitize tumors immunotherapy. As our understanding evolves, it becoming increasingly clear multifaceted approach integrating TME-targeted interventions with necessary overcome improve patient outcomes. Future research should focus on elucidating molecular mechanisms underlying senescence-driven resistance, identifying robust biomarkers predict treatment response, developing novel synergize ICIs. By harnessing approaches, we can expand scope efficacy immunotherapy, ultimately leading improved survival quality life for patients.

Language: Английский

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Non-oncogene dependencies: Novel opportunities for cancer therapy

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 228, P. 116254 - 116254

Published: May 3, 2024

Language: Английский

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Reprogramming cellular senescence in the tumor microenvironment augments cancer immunotherapy through multifunctional nanocrystals

Science Advances, Journal Year: 2024, Volume and Issue: 10(44)

Published: Nov. 1, 2024

Harnessing the immunogenic potential of senescent tumor cells provides an opportunity to remodel microenvironment (TME) and boost antitumor immunity. However, this needs be sophisticatedly wielded avoid additional immunosuppressive capacity cells. Our study shows that blocking JAK2/STAT3 pathway enhances efficacy Aurora kinase inhibitor alisertib (Ali)-induced senescence by reducing senescence-associated secretory phenotype (SASP) while preserving SASP. Hypothesizing SASP reprogramming with Ali JAK2 ruxolitinib (Rux) will benefit cancer immunotherapy, we create nanoparticulate crystals (Ali-Rux) composed Rux a fully active pharmaceutical ingredient. Immunization Ali-Rux-orchestrated promotes stronger activation antigen-presenting cells, enhancing immune surveillance. This approach remodels TME increasing CD8

Language: Английский

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