Researchers modeled a tiny mitochondrial peptide called SHLP6 and found it folds stably and can stick to proteins involved in cell death and brain health. In zebrafish larvae, giving SHLP6 lowered stress‑induced damage, boosted antioxidant enzymes, improved movement, and reduced harmful protein clumps. The work is still early‑stage and done in fish, not people.

Small humanin-like peptide-6 (SHLP6), is derived from the mitochondrial genome. The 3D structure of SHLP6 was evaluated using PEPstr, with homology modeling predicting a Cyt-C structure with a DOPE score of -645.717 and a GA341 score of 0.2832. The analysis showed that 96.5 % of residues were in favored regions in the Ramachandran plot, indicating a stable protein conformation. Molecular docking studies revealed that SHLP6 has binding affinities with apoptotic proteins such as Caspase 8 (-77.6 ± 2.9 kcal/mol), Bcl-2 (39.2 ± 15.3 kcal/mol), Bax (43.6 ± 7.7 kcal/mol), Cyt-C (-53.2 ± 8.7 kcal/mol), and CAT (-62.5 ± 1.3 kcal/mol). The interaction of SHLP6 with DRP1 (-47.7 ± 1.9 kcal/mol) was found to promote apoptosis, while interactions with SIRT1 (-49.1 ± 4.7 kcal/mol), IGF-1 (-58.7 ± 3.6 kcal/mol), and INSR (-66.4 ± 3.4 kcal/mol) suggest a potential role in controlling neurodegeneration. Molecular dynamics simulations confirmed the compact conformation of Caspase-8, high structural stability of SIRT1, and flexibility of DRP1. Treatment with SHLP6 (40 μg/ml) reduced developmental toxicity and improved antioxidant enzyme levels (SOD and CAT) in stress-induced zebrafish larvae. SHLP6 treatment also improved AChE levels in H₂O₂-exposed zebrafish larvae. SHLP6 treatment upregulated SOD, CAT, PRKN, p62, LCIII, SIRT1 and NDUFS4 genes, while modulating inflammation by downregulating TNF-α through IL-10 upregulation. SHLP6 efficiently restored locomotory activity in stress-induced zebrafish larvae. FTIR analysis indicated alterations in the secondary structure of proteins, and Congo red staining showed a 10 % decrease in BSA aggregation with SHLP6 treatment. These findings suggest that SHLP6 can be a promising therapeutic agent in enhancing antioxidant defenses, restoring mitochondrial health, and modulating inflammatory responses to mitigate oxidative stress-induced cellular dysfunction.