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Characterized by the presence of hemophagocytic macrophages and a fulminant cytokine storm, sHLH\/MAS leads to hyperferritinemia and multiorgan failure and rapidly progresses to death. The high mortality rate and the lack of specific treatments necessitate the development of a new drug. However, the complex and largely unknown immunopathologic mechanisms of sHLH\/MAS, which involve dysfunction of various immune cells, diverse etiologies, and different clinical contexts make this effort challenging. This review introduces the terminology, diagnosis, and clinical features of sHLH\/MAS. From a translational perspective, this review focuses on the immunopathological mechanisms linked to various etiologies, emphasizing potential drug targets, including key molecules and signaling pathways. We also discuss immunomodulatory biologics, existing drugs under clinical evaluation, and novel therapies in clinical trials. This systematic review aims to provide insights and highlight opportunities for the development of novel sHLH\/MAS therapeutics.<\/jats:p>","DOI":"10.1038\/s12276-024-01182-6","type":"journal-article","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T08:02:26Z","timestamp":1709712146000},"page":"559-569","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Immunopathology of and potential therapeutics for secondary hemophagocytic lymphohistiocytosis\/macrophage activation syndrome: a translational perspective"],"prefix":"10.1038","volume":"56","author":[{"given":"Tram T. 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