Background: This study aimed: (1) to compare the transcriptome profile of articular cartilage in cam-FAI (early stage) to advanced OA secondary to cam-FAI (late stage) and (2) to investigate epigenetic changes through the expression of DNA methylation enzymes DNMT3B, DNMT1, and DNMT3A and peroxisome proliferator-activated receptor gamma (PPARγ) in human cartilage samples during the progression of hip OA. Methods: Full-thickness cartilage samples were collected from the anterolateral head-neck junction (impingement zone) of 22 patients (9 early-FAI and 13 late-FAI). RNA sequencing and in vitro cartilage cultures with histological analysis and immunohistochemistry staining for PPARγ and DNMT3B were performed. Target gene validation was confirmed with RT-PCR. Results: Fifty genes and 42 pathways were identified differentially between early and late-FAI (fold change <–1.5 or >1.5, P <.01). PPARγ and DNMT3B were gradually suppressed with disease progression. Contrarily, disease progression induced expression of DNMT1/3A. Conclusion: By comparing comprehensive gene expression in early and late stage hip degeneration at the whole-genome level, distinct transcriptome profiles for early and late stage disease were identified along with key molecular contributors to the progression of hip OA. Preservation of endogenous PPARγ may have therapeutic potential to delay or prevent hip OA.