FOXO4-DRI vs MOTS-c

FOXO4-DRI

FOXO4-DRI is a 46-residue D-retro-inverso peptide designed to interfere with the interaction between the FOXO4 protein and p53. It was reported in 2017 by Baar and colleagues, who took part of the FOXO4 p53-interaction domain, joined it to a cell-penetrating sequence and built the whole peptide from D-amino acids. All published work is preclinical: cultured human cells, mouse models of ageing and of lung fibrosis, and one rodent study in which clearing senescent cells made pulmonary haemodynamics worse. No human study was identified.

MOTS-c

MOTS-c is a 16-residue peptide encoded by a short open reading frame within the mitochondrial gene for 12S ribosomal RNA. It belongs to the mitochondrial-derived peptides, a small group that also includes humanin, which is encoded in the 16S rRNA gene. Since it was first described in the mid-2010s it has been studied mainly in cultured cells and in mice, with attention to glucose and lipid handling in skeletal muscle and to cellular responses to metabolic stress. Human data are limited and consist mostly of measurements of its circulating levels in observational studies.

How FOXO4-DRI acts

Baar and colleagues reported in 2017 that FOXO4 holds p53 in the nucleus of senescent cells, and that a peptide competing for that interaction causes p53 to leave the nucleus, followed by apoptosis in senescent cells selectively. Solution NMR work published in 2025 placed the binding site on the disordered transactivation domain of p53 and found that both the FOXO4-derived region and the cationic carrier sequence contribute. Selectivity for senescent cells is reported by several groups, in cell and rodent models only.

How MOTS-c acts

The first cell and mouse studies reported that MOTS-c inhibits the folate pathway and, with it, de novo purine synthesis, so that the purine intermediate AICAR accumulates. This nucleotide mimics AMP and activates AMP-activated protein kinase (AMPK), a sensor of cellular energy status. Later work reported that under metabolic or oxidative stress the peptide moves from the cytoplasm into the nucleus, where it associates with transcription factors including NRF2 and alters the expression of stress-response genes. Most of this mechanistic evidence comes from cell and rodent models, and human mechanistic data are scarce.

The records side by side

• Type: FOXO4-DRI, D-retro-inverso peptide; MOTS-c, Mitochondrial-derived peptide (MDP)
• Length: FOXO4-DRI, 46 amino acids; MOTS-c, 16 amino acids
• Molecular weight: FOXO4-DRI, 5358 g/mol; MOTS-c, 2174.6 g/mol
• Molecular formula: FOXO4-DRI, C228H388N86O64; MOTS-c, C101H152N28O22S2

Reading a comparison

A comparison places two records side by side; it does not merge them. Each description above is drawn from that compound's own record, and the two were not necessarily characterised by the same methods, at the same time, or to the same level of detail. Before comparing any attribute, it is worth establishing that both records describe the substance you think they describe — names are not identifiers, and two entries sharing a name can differ in salt form, stereochemistry or the convention used to state a mass. Where a figure carries no method beside it, the comparison is between two reported numbers rather than between two measurements.