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Insulin resistance (IR) attributed by the deficiency of lipophagy, is an abnormal state of downregulation of insulin-mediated glucose uptake and use into the liver. Chromosome 9 open reading frame 72 (C9orf72) variously modulates autophagy. We investigated the role and the downstream pathway of C9orf72 in hepatic IR. We found that C9orf72 knockdown alleviated hepatic IR by lipophagy promotion in T2DM mice and in IR-challenged hepatocytes in vitro. C9orf72 interacted with and activated cell division cycle 42 (Cdc42) protein in IR-challenged hepatocytes, Which in turn, inhibits lipophagy by promoting neural Wiskott-Aldrich syndrome protein (N-WASP) expression and activation. C9orf72 inhibited lipophagy by activating the Cdc42/N-WASP axis to facilitate hepatic IR; therefore, the knockdown of C9orf72 may be potentially therapeutic for the treatment of IR. • Knockdown of C9orf72 alleviated hepatic insulin resistance via facilitating lipophagy in T2DM mice and in insulin resistance-challenged hepatocytes in vitro. • C9orf72 interacted with and activated Cdc42 in insulin resistance-challenged hepatocytes. • The activation of Cdc42 inhibited lipophagy in insulin resistance-challenged hepatocytes via enhancing N-WASP expression and activation. [ABSTRACT FROM AUTHOR]