Angiotensin (1-7) vs Foxo4-DRI

Binds Mas receptor (MasR), activating nitric oxide synthase and reducing oxidative stress. Opposes TGF-β and angiotensin II signaling to reduce fibrosis. Enhances insulin sensitivity and provides cardiovascular protection.

Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide hormone generated primarily through cleavage of angiotensin II by ACE2, functioning as a counter-regulatory arm of the renin-angiotensin system (RAS) by binding the Mas receptor to promote vasodilation, anti-fibrotic, anti-inflammatory, and cardioprotective effects that oppose the vasoconstrictive actions of angiotensin II. Ang-(1-7) acts through the ACE2/Mas receptor axis to reduce oxidative stress, attenuate NF-kB-mediated inflammation, and suppress TGF-beta fibrosis signaling; the ACE2/Ang-(1-7)/Mas axis has emerged as a key regulatory pathway in cardiovascular and metabolic disease, and gained renewed research attention given ACE2's role as the SARS-CoV-2 entry receptor. A Phase 1-2 randomized clinical trial of Ang-(1-7) infusion in COVID-19 ICU patients reported preliminary safety, tolerability, and dose-response data, providing the primary indexed human pharmacokinetic evidence; broader cardiovascular protective applications are supported by preclinical data but have not been established by completed Phase 3 trials. Ang-(1-7) has no FDA approval and no approved therapeutic indication in any jurisdiction; it is an endogenous peptide under active clinical investigation as a candidate for cardiovascular, metabolic, and inflammatory conditions, with emerging human safety data but an incomplete evidence base for any specific approved clinical use.

D-retro-inverso peptide that disrupts Foxo4/p53 interaction in senescent cells; restores p53-mediated apoptosis selectively in senescent cells; clears cellular "zombie cells"

FOXO4-DRI is a synthetic D-amino acid retro-inverso (DRI) peptide that disrupts the interaction between the FOXO4 transcription factor and p53 in senescent cells, triggering apoptosis selectively in cells with an activated senescent secretory phenotype (SASP) while sparing non-senescent cells in which this interaction is not tonically antiapoptotic. In senescent cells, overexpressed FOXO4 sequesters p53 in the nucleus and prevents it from initiating apoptosis, enabling the persistence of metabolically active senescent cells that secrete pro-inflammatory SASP cytokines; FOXO4-DRI competitively disrupts this FOXO4-p53 interaction, freeing p53 to activate its apoptotic transcriptional program specifically in cells where the FOXO4 sequestration is functionally relevant. The foundational study published in Cell demonstrated that FOXO4-DRI selectively induced apoptosis in senescent cells in vivo in mice, restoring tissue homeostasis in both chemotherapy-induced and naturally aged animals; subsequent molecular modeling work has characterized the FOXO4-TP53 interaction interface to guide further senolytic peptide design, though published evidence in humans is absent and the preclinical literature remains limited. FOXO4-DRI is a research compound with no regulatory approval in any jurisdiction; it has been studied only in preclinical animal models, and no human pharmacokinetic, safety, or clinical efficacy data has been established.