Vertical inhibition of PI3K/Akt/mTOR signaling demonstrates in vitro and in vivo anti-fibrotic activity.

•BEZ235 leads to superior inhibitory effect to rapamycin for dermal fibrosis in two complementary systemic sclerosis mouse models.•BEZ235 attenuates dermal fibrosis by vertical inhibiting PI3K/Akt/mTOR signaling via suppression of fibroblast activation.•Feedback induction of phosphorylation of the Akt on Ser473 by single mTOR inhibitor rapamycin might hamper its anti-fibrotic effect.•The strategy with BEZ235 overcomes the limitation of rapamycin in feedback activation of p-Akt on Ser473 following TGF-β treatment.