7-Ketocholesterol Links Sterol Homeostasis to Hedgehog Signaling and Stress–Survival Responses in MSCs from Patients with Acute Myeloid Leukemia

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Abstract
7-ketocholesterol (7-KC) is a bioactive oxysterol generated under oxidative stress and may contribute to bone marrow niche reprogramming in acute myeloid leukemia (AML), thereby promoting stress tolerance and therapeutic resistance Bone marrow mesenchymal stromal cells (MSCs) from healthy donors and AML patients were exposed to subtoxic 7-KC concentrations for 24 h. We evaluated the ABC transporters involved in lipid transport, multidrug resistance and membrane microdomain remodeling; Hedgehog pathway proteins; stress–survival signaling; redox balance by glutathione measurements, and mitochondrial function and dynamics, including membrane potential and gene expression of mitochondrial fission and fusion regulators. Results were integrated using principal component analysis (PCA), heatmaps, and correlation-based networks. Multivariate analyses revealed an integrated, lineage-dependent response. Healthy donor MSCs showed greater plasticity of the efflux and microdomain axis and higher oxidative and mitochondrial vulnerability at high 7-KC doses. AML-MSCs exhibited a basal preconditioned state phenotype and preferentially routed the response toward Hedgehog and stress–survival modules, accompanied by glutathione expansion and adaptive mitochondrial remodeling. 7-KC acts as a broad modulator of several MSC functions, linking sterol homeostasis to Hedgehog signaling, stress–survival pathways, redox balance, and mitochondrial remodeling, potentially supporting a pro-survival, more therapy-tolerant leukemic niche.
Funding Information
  • Instituto de Investigação em Imunologia
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (408685/2024-7)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2025/26983-8)

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