AbstractObjectiveOur previous study reveals that proprotein convertase subtilisin/kexin type 9 (PCSK9) is positively related to inflammatory markers, T helper (Th)‐17 cells, and treatment response in ankylosing spondylitis (AS) patients. Subsequently, this study aimed to explore the effect of PCSK9 on Th cell differentiation and its potential molecular mechanism in AS.MethodsSerum PCSK9 was determined by enzyme‐linked immunosorbent assay in 20 AS patients and 20 healthy controls (HCs). Then naïve CD4+T cells were isolated from AS patients and infected with PCSK9 overexpression or knockdown adenovirus followed by polarization assay. Afterward, PMA (an NF‐κB activator) was administrated.ResultsPCSK9 was increased in AS patients compared to HCs (p< .001), and it was positively related to Th1 cells (p= .050) and Th17 cells (p= .039) in AS patients. PCSK9 overexpression increased the CD4+IFN‐γ+cells (p< .05), CD4+IL‐17A+cells (p< .01), IFN‐γ (p< .01), and IL‐17A (p< .01), while it exhibited no effect on CD4+IL‐4+cells or IL‐4 (bothp> .05); its knockdown displayed the opposite function on them. Moreover, PCSK9 overexpression upregulated the p‐NF‐κB p65/NF‐κB p65 (p< .01), while it had no effect on p‐ERK/ERK or p‐JNK/JNK (bothp> .05); its knockdown decreased p‐NF‐κB p65/NF‐κB p65 (p< .01) and p‐JNK/JNK (p< .05). Then, PMA upregulates p‐NF‐κB p65/NF‐κB p65 (p< .001) and increased CD4+IFN‐γ+cells, CD4+IL‐17A+cells, IFN‐γ, and IL‐17A (allp< .01), also it alleviated the effect of PCSK9 knockdown on NF‐κB inhibition and Th cell differentiation (allp< .01).ConclusionPCSK9 enhances Th1 and Th17 cell differentiation in an NF‐κB‐dependent manner in AS, while further validation is necessary.