From collapse to comeback: Luteolin rejuvenates nucleus pulposus progenitor cells via SIRT1/ATF5-UPRmt to reverse intervertebral disc degeneration cascade.

Intervertebral disc degeneration (IVDD) is a major contributor to low back pain (LBP) and one of the foremost causes of disability worldwide. Oxidative stress-induced senescence of nucleus pulposus progenitor cells (NPPC) and mitochondrial dysfunction are key drivers of IVDD. The mitochondrial unfolded protein response (UPRmt), orchestrated by the Silent Information Regulator 1 (SIRT1)-Activating Transcription Factor 5 (ATF5) axis, plays a pivotal role in maintaining mitochondrial proteostasis. However, its involvement in IVDD remains insufficiently characterized. Luteolin (Lut), a naturally occurring flavonoid with well-documented antioxidant and anti-senescence properties, has emerged as a promising disease-modifying candidate. We employed an integrated approach combining network pharmacology, molecular docking, and Mendelian randomization to identify and validate SIRT1 as a central target of Lut in IVDD. Human nucleus pulposus (NP) tissues spanning Pfirrmann grades II-V were analyzed to assess the expression of SIRT1 and UPRmt-related proteins. Functional assays in TBHP-induced NPPC senescence models were conducted to evaluate the effects of Lut on proliferation, senescence, mitochondrial function, and UPRmt activation, with or without SIRT1 knockdown. Finally, a puncture-induced rat IVDD model was employed to assess the therapeutic efficacy of Lut with imaging, histological, and behavioral analyses. Human NP specimens exhibited a progressive decline in SIRT1, ATF5, and UPRmt effectors (HSP60, LONP1, CLPP) with advancing degeneration grades. Lut was found to directly bind SIRT1, thereby stabilizing mitochondrial function and alleviating NPPC senescence through activation of the SIRT1-ATF5-UPRmt pathway. Genetic silencing of SIRT1 abolished the protective effects of Lut on cellular senescence, UPRmt activation, and bioenergetics. In vivo, Lut administration attenuated disc height loss, preserved extracellular matrix integrity and partially alleviated pain-like behaviors in rats with IVDD. This study establishes SIRT1 as a central therapeutic target of Lut and underscores the SIRT1-ATF5-UPRmt axis as a critical mechanism mediating its protective effects. By restoring mitochondrial proteostasis and delaying NPPC senescence, Lut emerges as a promising disease-modifying strategy for IVDD management.