Zhou et al. [128] found that inhibitor of PI3K/Akt, LY294002, and the classic mTOR inhibitor rapamycin could both significantly suppress the HIF-1a up-regulation [129], CTGF [130], and collagen I, are all conceived as crucial cytokines involved in the dermal fibrosis of scleroderma, demonstrating that PI3K/Akt/mTOR/HIF-1a-mediated fibrogenesis was critically participated in the activation of SSc fibroblasts. The gene discussed is CCN2; the disease is scleroderma.