PHLPP1 Regulates Inflammatory Signaling in Degenerated Nucleus Pulposus Cells in Mice and Humans

Intervertebral disc degeneration is a major contributor to discogenic low back pain and is characterized by a pro-inflammatory and catabolic microenvironment within the nucleus pulposus. We previously showed that the phosphatase PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is positively correlated with intervertebral disc degeneration and that its deficiency promoted nucleus pulposus cell survival and matrix homeostasis; however, its role in inflammatory signaling during intervertebral disc degeneration remained unknown. Here, we show that PHLPP1 functions as an upstream regulator of inflammatory and catabolic networks in the degenerating intervertebral disc. In aged mice, Phlpp1 deficiency attenuated spontaneous intervertebral disc degeneration and reduced expression of IL1B and IL6. Notably, severe age-associated degeneration and inflammation were observed primarily in male wildtype mice, where the protective effects of Phlpp1 deletion were most apparent. To define the underlying mechanisms in human disease, we performed transcriptomic profiling of degenerated human nucleus pulposus cells following siRNA-mediated PHLPP1 silencing. PHLPP1 depletion induced widespread transcriptional reprogramming characterized by suppression of inflammatory cytokines, chemokines, and matrix-degrading enzymes, while promoting expression of extracellular matrix-associated genes. Pathway enrichment and network analyses identified coordinated inhibition of cytokine-cytokine receptor interaction, TNF, IL17, chemokine, and NFKB signaling pathways, revealing PHLPP1 as a central node linking cytokine amplification, immune cell recruitment, and matrix degradation. These findings were validated by reduced expression of IL1A, IL1B, IL6, CXCL2, CCL20, and STAT1, alongside increased ACAN expression. Furthermore, PHLPP1 silencing attenuated IL1B-induced inflammatory activation and matrix suppression and reduced STAT1 phosphorylation after IL1B stimulation. Collectively, our findings identify PHLPP1 as a critical regulator coupling inflammatory amplification to matrix remodeling in degenerating intervertebral discs and nominate PHLPP1 inhibition as a potential disease-modifying therapeutic strategy for intervertebral disc degeneration.