sirolimus
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.
Recent Publications Focus
Below is a summary of the newest research publications targeting sirolimus (sorted by publication date).
Recent research has explored sirolimus and related mTOR inhibitors across diverse cardiovascular and vascular diseases. In computational studies, rapamycin served as a control compound while screening for novel mTOR inhibitors to treat feline hypertrophic cardiomyopathy [42371166]. For atherosclerosis, rapamycin-encapsulated dendrimer nanoparticles targeting uPAR-enriched plaques significantly reduced plaque burden by 52% in whole aorta and necrotic core size by 68%, while suppressing proinflammatory cytokines including TNF-α and IL-6 and promoting fibrous cap thickening [42340987]. In venous malformations, polymeric rapamycin nanoparticles co-encapsulating ponatinib achieved 70% lesion regression over 20 days in a murine model with a 6.3-fold reduction in blood vessels, demonstrating the potential of nanoparticle-based combination therapy [42090479]. For cardiac xenotransplantation, sirolimus and its analogues have been proposed as critical modulators to overcome missing self-rejection and attenuate cardiac hypertrophy, potentially addressing longevity mismatches between porcine grafts and human recipients [41909987]. Additionally, chronic rapamycin supplementation prevented age-related motor function decline in mice, with benefits associated with reduced protein carbonyls and ER stress-mediated apoptosis in motor function brain regions [41863332].
Sirolimus demonstrates efficacy in immunomodulatory applications, particularly in transplantation and immune-mediated disorders. Sirolimus-based treatment regimens showed benefit in patients with antinuclear antibody-positive immune thrombocytopenia [42179326], while children with kaposiform hemangioendothelioma receiving sirolimus successfully tolerated catch-up vaccinations with preserved vaccine-induced immune competence, evidenced by seroprotective antibody responses comparable to healthy controls and notably higher proportions of IgG+ memory B cells [42154819]. In allogeneic hematopoietic cell transplantation, sirolimus combined with posttransplant cyclophosphamide and the Aurora kinase A inhibitor VIC-1911 achieved zero cases of grade 3-4 acute graft-versus-host disease and only 6% moderate/severe chronic GVHD with 0% relapse through 1 year, demonstrating effective suppression of CD28 signaling downstream pathways [41592279]. Rapamycin-modified tolerogenic dendritic cells have also been investigated to induce liver graft tolerance through MHC-II+CD8+ regulatory T cell mechanisms [42008782].
Advanced drug delivery strategies have emerged to enhance rapamycin's bioavailability and therapeutic efficacy. Rapamycin-loaded core-multishell nanocarriers with redox-induced drug release have been developed for topical skin application, with differential penetration patterns revealing distinct transport mechanisms between drug and carrier [41786093]. Biomolecular condensates composed of hydra-elastin-like polypeptides fused to five FKBP domains were engineered as GRP78-targeted intracellular carriers for rapamycin delivery, demonstrating enhanced cellular association and superior inhibition of mechanistic target of rapamycin signaling in breast cancer cells compared to untargeted formulations [41954390]. In organ preservation, rapamycin was incorporated into a defatting pharmacologic cocktail for ex situ perfusion of marginal liver grafts, building on evidence that rapamycin reduces triglyceride content in steatotic hepatocytes [42148871].
Hepatotoxicity remains an important safety consideration with mTOR inhibitors. Metabolomic and transcriptomic analyses in zebrafish models revealed that sirolimus and everolimus caused hepatotoxicity even at standard doses, with pronounced effects at higher concentrations including reduced liver size, elevated ALT levels, and increased hepatocyte vacuolization associated with aberrant PI3K/Akt pathway activation and disrupted lipid metabolism [41320894]. These findings underscore the importance of regular monitoring of drug blood concentrations in pediatric patients receiving sirolimus therapy and highlight the need for improved dose optimization strategies.