sirolimus

Overview

Sirolimus, also known as rapamycin, is a macrolide compound used primarily as an immunosuppressive and mTOR pathway inhibitor. It binds to FKBP12 and functionally suppresses mechanistic target of rapamycin complex 1 (mTORC1), thereby altering cell growth, proliferation, metabolism, and immune activation. Because of these effects, sirolimus has broad biomedical relevance in transplantation, hematology, vascular anomalies, and experimental aging research.

Clinically, sirolimus is used in regimens that require immune modulation, including hematopoietic cell transplantation and graft-versus-host disease prophylaxis, and it has also been investigated for difficult-to-treat pediatric vascular tumors and malformations such as kaposiform hemangioendothelioma and venous malformations. In recent research, it has also served as a pharmacologic probe for mTORC1-dependent biology in cancer, autophagy, and tissue remodeling, including pathways involving PI3K/AKT/mTOR signaling, AKT serine/threonine kinase 1, PRKAA1, SQSTM1, and related regulators such as everolimus and melatonin.

Focus of Latest Publications

Recent publications explore sirolimus and related mTOR inhibitors across immunosuppression, vascular disease, aging, and formulation optimization. In transplantation, sirolimus-based regimens have been examined for preventing graft-versus-host disease following myeloablative hematopoietic cell transplantation when combined with post-transplant cyclophosphamide and Aurora kinase A inhibition, demonstrating low rates of acute and chronic GVHD with favorable clinical outcomes. Additionally, rapamycin-modified dendritic cells are being investigated to induce liver graft tolerance, and sirolimus-based treatments have been studied for antinuclear antibody-positive immune thrombocytopenia. Notably, children receiving sirolimus for kaposiform hemangioendothelioma tolerate vaccinations well, with preserved seroprotective antibody responses and vaccine-induced immune competence comparable to healthy controls, supporting feasibility of timely immunization in immunocompromised pediatric populations.

Cardiovascular and vascular applications represent a major research focus. Sirolimus and other mTOR inhibitors are proposed as strategies to overcome "missing self" rejection and mitigate cardiac hypertrophy in porcine-to-human cardiac xenotransplantation, with potential additional benefits for healthy aging and longevity extension. In preclinical studies, rapamycin-encapsulating nanoparticle formulations combined with kinase inhibitors have achieved significant venous malformation regression through PI3K/AKT/mTOR pathway inhibition. The mTOR pathway also represents a therapeutic target in rare lung diseases; although rapamycin reduces lung function loss in lymphangioleiomyomatosis, some patients continue to decline, indicating a need for adjunctive therapeutic approaches.

Emerging evidence demonstrates mTOR inhibition benefits aging-related functional decline. Chronic rapamycin supplementation prevented age-related motor function deterioration in mice, with stronger effects in females, and these improvements correlated with reduced protein oxidative damage and attenuated endoplasmic reticulum stress in motor function-related brain regions, consistent with rapamycin's established role in senolytic and healthy aging pathways.

Parallel efforts focus on optimizing drug delivery and safety profiles. Novel delivery systems including nanocarrier formulations, biomolecular condensates, and polymeric drug conjugates are being developed to enhance rapamycin's solubility, bioavailability, and cellular targeting—including GRP78-directed intracellular delivery to stress-responsive cancer cells and topical nanocarrier systems for skin penetration. However, metabolomic and transcriptomic analyses revealed that sirolimus and everolimus induce hepatotoxicity through PI3K/AKT dysregulation and impaired lipid metabolism, with implications for therapeutic drug monitoring in pediatric populations and underscoring the importance of balancing efficacy against hepatic safety.

Key Publications

• NEWJun In Silico Discovery of mTOR Inhibitors as Potential Therapeutics for Feline Hypertrophic Cardiomyopathy. (Journal of molecular modeling, 2026, PMID 42371166): "Both molecular dynamics (MD) simulation and MM/PBSA calculations indicated that the screened compound, dihydro-alpha-ergocryptine, exhibited a higher binding affinity and stability with feline mTOR compared to rapamycin."
• May Sirolimus-based treatment regimens for antinuclear antibody (ANA)-positive immune thrombocytopenia: a retrospective single-center cohort study. (Hematology (Amsterdam, Netherlands), 2026, PMID 42179326): "To evaluate the efficacy and safety of sirolimus-based treatment regimens in patients with antinuclear antibody (ANA)-positive immune thrombocytopenia (ITP)."
• May Antibody levels and immune memory in children with kaposiform hemangioendothelioma treated with sirolimus after catch up vaccination. (Human vaccines & immunotherapeutics, 2026, PMID 42154819): "This study evaluated the safety, immunogenicity, and post-vaccination immune responses of timely, sequential catch-up vaccination in children with Kaposiform hemangioendothelioma (KHE) undergoing sirolimus treatment."
• Feb Effect of a defatting pharmacologic cocktail with rapamycin during cold-to-warm ex situ perfusion of discarded human livers: A comparative study. (Surgery, 2026, PMID 42148871): "we demonstrated that a pharmacologic defatting cocktail with rapamycin (DFAT) significantly reduced the triglyceride content of steatotic hepatocytes in vitro."
• May Polymeric rapamycin nanoparticles encapsulating ponatinib cause regression of venous malformations in mice. (Science translational medicine, 2026, PMID 42090479): "Daily oral administration of rapamycin (RAPA), an mTOR pathway inhibitor, has limited effectiveness in promoting lesion regression in patients with TEK receptor tyrosine kinase (TIE2)-mutated VMs."
• May Rapamycin-modified novel tolerogenic dendritic cells induce liver graft tolerance through MHC-II+CD8+ regulatory T cells. (Hepatology communications, 2026, PMID 42008782): "Rapamycin-modified novel tolerogenic dendritic cells induce liver graft tolerance through MHC-II+CD8+ regulatory T cells."
• May Lysosomal accumulation of masitinib alters autophagy via pH-dependent trapping. (European journal of pharmacology, 2026, PMID 42009094): "Across multiple cell lines, masitinib suppresses mTORC1 signaling while paradoxically inducing AKT phosphorylation through a VPS34 and rapamycin-sensitive pathway independent of class I PI3K."
• May Intracellular GRP78-Directed Delivery of Rapamycin by Biomolecular Condensates of Hydra-Elastin-like Polypeptides. (Biomacromolecules, 2026, PMID 41954390): "Rapamycin (Rapa) is a potent inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) with possible applications in multiple diseases; however, it and its analogues exhibit low solubility, variable bioavailability, and dose-limiting side effects."
• Apr Sirolimus and Mimetics: Modulator Sine Qua Non for Cardiac Xenotransplantation? (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 41909987): "It is amenable to inhibition by sirolimus and other mammalian target of rapamycin (mTOR) signaling suppressors."
• Apr Chronic rapamycin treatment attenuates age-related motor deficits in sex-dependent manner in UM-HET3 mice. (The journals of gerontology. Series A, Biological sciences and medical sciences, 2026, PMID 41863332): "Interventions Testing Program identified rapamycin as a robust lifespan-extending agent at multiple testing sites and in both sexes, with particularly strong effects in females, making it a leading candidate in aging research."