Previous studies have shown that orlistat can effectively inhibit the proliferation, invasion, and migration of colon cancer cells.[43, 44] In our study, orlistat interfered with the interaction between HACD2 and PRKN by binding to HACD2 (KD = 0.13 μm), which further inhibited the expression of PKM2 and c‐Myc and reduced the proliferation of PC cells, especially in combination with gemcitabine (GEM) (Figure 7). Here, PKM is linked to malignant colon neoplasm.