Hepatocyte growth factor suppresses melanogenesis via ERK-dependent nuclear exclusion of MITF

Background: Hepatocyte growth factor (HGF) has been considered a promising candidate for improving skin and hair quality. Solar lentigines-the most common UV-associated hyperpigmentary skin disorder-have historically been thought to involve HGF in their pathogenesis. However, the precise role of HGF in cutaneous melanogenesis remains unclear, and direct experimental evidence supporting its melanogenic function is lacking. This study aimed to systematically investigate the effects of HGF on melanogenesis and to elucidate the underlying molecular mechanisms.

Result: HGF is predominantly expressed in dermal fibroblasts, whereas its receptor c-Met is highly expressed in melanocytes, particularly in human melanocytes. Unexpectedly, HGF significantly suppressed melanin production in mouse and human melanocytes, while promoting the survival and proliferation of human melanocytes. Mechanistically, HGF downregulated the expression of melanogenic Enzymes, Tyrosinase, Tyrp1, and DCT, without altering MITF expression. Instead, HGF activated ERK signaling, which inhibited nuclear translocation of MITF, thereby suppressing melanogenic gene expression. Consistent with in vitro findings, topical application of HGF significantly reduced epidermal melanin accumulation in KRT14-SCF transgenic mice and attenuated UVB-induced pigmentation in ex vivo cultured human skin.

Conclusions: These findings overturn the prevailing view of HGF as a melanogenic factor and identify HGF as a negative regulator of melanogenesis. Given its pro-survival effects on melanocytes, HGF may represent a promising preventive topical strategy for photoaging-associated hyperpigmentation without increasing the risk undesired melanocyte loss.