In lab tests, the mitochondrial peptide humanin (as the HNG version) stopped the cancer drug venetoclax from slowing bone growth in rat bone cultures and human growth‑plate samples, but a single dose didn’t rescue bone growth in a short‑term mouse study, so the effect isn’t proven in living animals yet.

Recent preclinical studies reported that the BCL-2 inhibitor venetoclax can impair bone growth. A strategy to prevent such a side effect of this promising anticancer drug is highly desired. Earlier <i>in vitro</i> and <i>in vivo</i> studies suggested that the mitochondrial peptide humanin has the potential to prevent drug-induced growth impairment. We hypothesized that co-treatment with the humanin analog HNG may prevent venetoclax-induced bone growth impairment. <i>Ex vivo</i> studies were performed in fetal rat metatarsal bones and human growth plate samples cultured for 12 and 2&#x2005;days, respectively, while <i>in vivo</i> studies were performed in young neuroblastoma mice being treated daily for 14&#x2005;days. The treatment groups included venetoclax, HNG, venetoclax plus HNG, or vehicle. Bone growth was continuously monitored and at the end point, histomorphometric and immunohistochemical analyses were performed in fixed tissues. Venetoclax suppressed metatarsal bone growth and when combined with HNG, bone growth was rescued and all histological parameters affected by venetoclax monotherapy were normalized. Mechanistic studies showed that HNG downregulated the pro-apoptotic proteins Bax and p53 in cultured metatarsals and human growth plate tissues, respectively. The study in a neuroblastoma mouse model confirmed a growth-suppressive effect of venetoclax treatment. In this short-term <i>in vivo</i> study, no significant bone growth-rescuing effect could be verified when testing HNG at a single dose. We conclude that humanin dose-dependently protects <i>ex vivo</i> cultured metatarsal bones from venetoclax-induced bone growth impairment by restoring the growth plate microstructure.