The 2-methoxyestradiol (2-ME), a natural endogenous metabolite of 17b-estradio, reduced HIF-1a, CTGF, and collagen I induced by hypoxia via PI3K/Akt/mTOR/HIF-1a and inhibited the proliferation of fibroblasts, which is expectable to become a promising agent to treat scleroderma [131]. The gene discussed is HIF1A; the disease is scleroderma.