bims-cesemi 2025-10-26 papers

Cancer Discov. 2025 Oct 27.

P21-positive senescent stromal cells promote prostate cancer immune suppression and progression that can be reversed by senolytic therapy.

Cellular senescence is a well-established tumor-suppressive cell cycle arrest program. However, chronic inflammation through the senescence-associated secretory phenotype (SASP) can alternatively drive immune suppression and cancer progression. Using prostate cancer patient samples and murine models, we find p16+ and p21+ senescent cells accumulate throughout malignant progression and associate with immune suppression. Single cell sequencing revealed p16 and p21 mark distinct epithelial and stromal senescent populations, with p21+ non-tumor cells expressing the highest SASP. p21+ stromal cell removal blocked the SASP to reverse immune suppression and slow tumor growth. Senolytic BCL-xL inhibitor treatment could clear p21+ stromal senescent cells, reactivating anti-tumor CD8+ T cell immunity and inhibiting prostate tumor progression in mice. Suppression of BCL-xL or p21 also potentiated anti-PD-1 ICB in preclinical prostate cancer models. Our findings demonstrate that targeting p21+ senescent stromal populations can yield therapeutic benefits in advanced prostate cancer through activating anti-tumor immunity and enhancing immunotherapy outcomes.

DOI: https://doi.org/10.1158/2159-8290.CD-25-1212

Commun Biol. 2025 Oct 20. 8(1): 1485

SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence.

Zhang Xianhong, Gao Yue, Zhang Yu, Zhang Yichen, Chen Yufei, Pei Xinke, Zhang Jinhui, Wang Yiqi, Du Yitian, Hao Shuailin, Ni Ting.

Protein lysine succinylation is a crucial post-translational modification that regulates nearly all aspects of eukaryotic and prokaryotic cell, including gene transcription, cell metabolism and redox homeostasis. Among them, metabolic disorders caused by dysfunctional post-translational modifications induce aging and aged-related diseases, including cancer. This study quantified the dynamic changes in protein succinylation in response to DNA damage stress induced by etoposide (ETOP) in tumor cells. A total of 4354 lysine succinylation sites on 1259 proteins were identified, many of which have not been previously reported. Bioinformatics analysis revealed that many proteins are involved in the metabolism of nicotinamide adenine dinucleotide phosphate (NADPH) in mitochondria (including MTHFD2). We further found that low activity or depletion of MTHFD2 enhances the degree of TIS in breast cancer cells and decreases their resistance to chemotherapeutic agents. Interestingly, we also found that SIRT5-mediated desuccinylation of MTHFD2 was able to reduce the senescence of breast cancer cells, thereby enhancing their resistance to chemotherapeutic drugs. This effect may explain the poorer prognosis observed in breast cancer patients with high expression levels of SIRT5 or MTHFD2. These systematic analyses provide new insights into targeting succinylation-modified metabolic proteins to enhance TIS, and their combination with senolytics for breast cancer therapy.

DOI: https://doi.org/10.1038/s42003-025-08878-z

Nat Metab. 2025 Oct 20.

A lactate-acetate interaction between macrophages and cancer cells drives metastasis.

DOI: https://doi.org/10.1038/s42255-025-01398-4

Nature. 2025 Oct 23.

This luxury 'cat poo' coffee has a unique flavour: what's behind it?

Nicola Jones.

Keywords: Business; Chemistry; Metabolism

DOI: https://doi.org/10.1038/d41586-025-03467-w

Mol Biol Rep. 2025 Oct 25. 53(1): 12

Calcium dynamics unplugged: NCLX in disease and therapeutic frontiers.

Dhriti Majumder.

Mitochondrial ion channels and transporters are pivotal for cellular bioenergetics, signalling, and homeostasis, with the sodium-calcium-lithium exchanger (NCLX) emerging as a critical regulator of mitochondrial calcium dynamics. By extruding calcium in exchange for sodium or lithium ions, NCLX prevents calcium overload, a key contributor to mitochondrial dysfunction and cell death. While previous reviews have explored NCLX in the context of specific diseases or immune cell function, this article provides a comprehensive analysis of its role across multiple disease states, including cardiovascular, neurological, metabolic, and pregnancy-related conditions. Moreover, it highlights the potential of ethnobotanical compounds such as resveratrol and curcumin as therapeutic candidates targeting NCLX. By integrating insights from structural biology, disease mechanisms, and emerging therapeutic strategies, this review aims to advance our understanding of NCLX's role in pathophysiology and explore novel avenues for its targeted modulation in diseases characterized by disrupted mitochondrial calcium homeostasis.

Keywords: Calcium exchange; Cardiovascular diseases; Mitochondria; NCLX; NCLX targeting therapeutics; Neurodegeneration

DOI: https://doi.org/10.1007/s11033-025-11188-6

Nature. 2025 Oct 20.

Breastfeeding boosts immune cells that protect against breast cancer.

Starre Vartan.

Keywords: Cancer; Immunology

DOI: https://doi.org/10.1038/d41586-025-03419-4

Acta Pharm Sin B. 2025 Oct;15(10): 5294-5311

Succinylation of tumor suppressor PPP2R1A K541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling to display oncogene function.

Guang Yang, Yufei Wang, Hongfeng Yuan, Huihui Zhang, Lina Zhao, Chunyu Hou, Pan Lv, Jihui Hao, Xiaodong Zhang.

Metabolic reprogramming plays a central role in tumors. However, the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood. Here, we try to identify the mechanism by which histone acetyltransferase 1 (HAT1) confers reprogramming of gluconeogenesis/lipogenesis in liver cancer. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice. Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver. Protein phosphatase 2 scaffold subunit alpha (PPP2R1A) promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1 (PCK1) serine 90 dephosphorylation to suppress the tumor growth. HAT1 succinylated PPP2R1A at lysine 541 (K541) to block the assembly of protein phosphatase 2A (PP2A) holoenzyme and interaction with PCK1, resulting in the depression of dephosphorylation of PCK1. HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation, leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1 (SREBP1) nuclear accumulation-induced lipogenesis gene expression, which enhanced the tumor growth. In conclusion, succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer. Our finding provides new insights into the mechanism by which post-translational modifications (PTMs) confer the conversion of tumor suppressor function to oncogene.

Keywords: Gluconeogenesis; HAT1; Lipogenesis; Liver cancer; Metabolic remodeling; PCK1 phosphorylation; PPP2R1A; SREBP1; Succinylation

DOI: https://doi.org/10.1016/j.apsb.2025.07.040