Low-molecular-weight whey proteins promote collagen production in dermal fibroblasts via the TGF-β receptor/Smad pathway

Whey proteins (WPs) reportedly enhance cutaneous tissue regeneration in in vivo studies. However, the underlying mechanisms of such regenerative processes are poorly understood. In this study, we show that low-molecular-weight WPs (LMWPs; 1-30 kDa) accelerate the dermal collagen production via the transforming growth factor β receptor (TβR)/Smad pathway. We showed that LMWPs increased type I and III collagen expression in normal human dermal fibroblasts. Moreover, LMWPs rapidly induced Smad protein phosphorylation and nuclear translocation. Notably, type I TβR/Smad signaling inhibitor treatment or type II TβR siRNA knockdown blocked the LMWP-induced type I collagen expression. To identify the active components, we fractionated LMWPs and identified β-lactoglobulin and α-lactalbumin as potential TβR/Smad signaling inducers. Our findings unravel novel biological functions of WPs, involving the TβR/Smad-dependent induction of dermal collagen synthesis, highlighting the therapeutic potential of LMWPs in wound healing.