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  • Review Article
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Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis

Nature Reviews Cardiology volume 22, pages 149–164 (2025)Cite this article

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Abstract

Lysosomes have a central role in the disposal of extracellular and intracellular cargo and also function as metabolic sensors and signalling platforms in the immunometabolic reprogramming of macrophages and other immune cells in atherosclerosis. Lysosomes can rapidly sense the presence of nutrients within immune cells, thereby switching from catabolism of extracellular material to the recycling of intracellular cargo. Such a fine-tuned degradative response supports the generation of metabolic building blocks through effectors such as mTORC1 or TFEB. By coupling nutrients to downstream signalling and metabolism, lysosomes serve as a crucial hub for cellular function in innate and adaptive immune cells. Lysosomal dysfunction is now recognized to be a hallmark of atherogenesis. Perturbations in nutrient-sensing and signalling have profound effects on the capacity of immune cells to handle cholesterol, perform phagocytosis and efferocytosis, and limit the activation of the inflammasome and other inflammatory pathways. Strategies to improve lysosomal function hold promise as novel modulators of the immunoinflammatory response associated with atherosclerosis. In this Review, we describe the crosstalk between lysosomal biology and immune cell function and polarization, with a particular focus on cellular immunometabolic reprogramming in the context of atherosclerosis.

Key points

  • Lysosomes are centralized hubs for metabolic sensing and functional reprogramming of cells.

  • Lysosomal metabolic sensing governs immune cell homeostasis and function.

  • Lysosome dysfunction contributes to the immunoinflammatory response and metabolic impairment in vascular atherosclerotic lesions.

  • Lysosomes are a compelling target for the modulation of immune responses in atherosclerosis.

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Fig. 1: Lysosomes orchestrate macrophage metabolic reprogramming.
Fig. 2: Lysosomes govern the immunometabolic phenotype of lymphocytes.
Fig. 3: Macrophage lysosomes promote inflammation or its resolution in atherosclerosis.

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Acknowledgements

G.D.N. was supported by Progetti di Rilevante Interesse Nazionale (PRIN 2022 7KTSAT), Ricerca Finalizzata, Ministry of Health (RF-2019-12370896), Nanokos (European Commission Ref. EUROPEAID/173691/DD/ACT/XK), PNRR Missione 4 (Progetto CN3 — National Center for Gene Therapy and Drugs based on RNA Technology), PNRR Missione 4 (Progetto MUSA — Multilayered Urban Sustainability Action), PNRR Missione 6 (PNRR-MAD-2022-12375913) and CARDINNOV, Ministry of Research and University under the umbrella of the Partnership fostering a European Research Area for Health (ERA4Health) (GA number 101095426 of the EU Horizon Europe Research and Innovation Programme). F.B. was supported by Progetti di Rilevante Interesse Nazionale (PRIN 2022 2022NBKCWP), Fondazione Cariplo (1560-2019) and Piano di Sostegno alla Ricerca, Università degli studi di Milano (PSR2022_DIP_022_AZIONE_A_FBONA). L.Y.-C. was supported by grants from the European Research Council (ERC) consolidator programme (ERC2016COG724838), ANR (MacBurn) and IHU RespirERA (Respiratory Health, Environment and Ageing).

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Author notes

  1. These authors contributed equally: Laurent Yvan-Charvet, Babak Razani, Giuseppe D. Norata.

Authors and Affiliations

  1. Department of Excellence of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Milan, Italy

    Fabrizia Bonacina & Giuseppe D. Norata

  2. Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA

    Xiangyu Zhang & Babak Razani

  3. Pittsburgh VA Medical Center, Pittsburgh, PA, USA

    Xiangyu Zhang & Babak Razani

  4. Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, Paris, France

    Nicolas Manel

  5. Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d’Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Fédération Hospitalo-Universitaire (FHU), Oncoage, Nice, France

    Laurent Yvan-Charvet

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Contributions

F.B., X.Z. and N.M. researched data for the article. F.B., L.Y.-C. and G.D.N. discussed its content. F.B., X.Z., N.M., L.Y.-C. and G.D.N. wrote the manuscript. F.B., L.Y.-C., B.R. and G.D.N. reviewed and edited it before submission.

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Bonacina, F., Zhang, X., Manel, N. et al. Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis. Nat Rev Cardiol 22, 149–164 (2025). https://doi.org/10.1038/s41569-024-01072-4

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