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  3. Mitigating PCOS progression: The protective effect of C-phycocyanin on ovarian granulosa cell pyroptosis via the NRF2/NLRP3/GSDMD pathway

Mitigating PCOS progression: The protective effect of C-phycocyanin on ovarian granulosa cell pyroptosis via the NRF2/NLRP3/GSDMD pathway

  • Int Immunopharmacol. 2025 Jun 26:159:114917. doi: 10.1016/j.intimp.2025.114917.
Jing Zhang 1,  Yaxin Chen 2,  Baoqing Han 3,  Yang Liu 2,  Xuan Li 2,  Jun Yang 2,  Yajing Liu 2,  Yunxia Cao 4,  Dan Liang 5,  Biao Yu 6
Affiliations

Affiliations

  • 1 College of Grain Engineering, Anhui Vocational College of Grain Engineering, Hefei 230011, Anhui, China.
  • 2 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China.
  • 3 Belgorod Institute of Food Sciences, Dezhou University, Dezhou 253023, Shandong, China.
  • 4 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China. Electronic address: caoyunxia6@126.com.
  • 5 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China. Electronic address: ahmuxl@sina.com.
  • 6 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China. Electronic address: biaoyu@ahmu.edu.cn.
PMID: 40412127 DOI: 10.1016/j.intimp.2025.114917
Abstract

Background: Pyroptosis is a proinflammatory cell death process that contributes to inflammatory diseases. C-Phycocyanin (C-PC) is a water-soluble protein pigment primarily derived from cyanobacteria, and it exhibits anti-inflammatory effects. However, the role of natural C-PC in Pyroptosis in human ovarian granulosa cells (GCs), particularly in conditions like polycystic ovary syndrome (PCOS), remains unclear. This study investigates the effects of C-PC on Pyroptosis and its relevance to PCOS.

Methods: Here dehydroepiandrosterone (DHEA) was used to induce PCOS in a mouse model that was characterized by an irregular oestrous cycle, cystic follicles and an elevated serum hormone level. DHEA treatment was used to induce GC Pyroptosis. Scanning electron microscopy (SEM) was used to determine cell morphology. The expression levels of key proteins for oxidative stress and Pyroptosis, including nuclear factor erythroid 2-related factor 2 (NRF2), NLR family of pyrroline-containing structural domain 3 (NLRP3) inflammasomes, cleaved Caspase-1, and N-GSDMD were investigated in vivo and in vitro by Western blotting and immunofluorescence staining.

Results: C-PC restored the estrous cycle in PCOS mice, reduced testosterone levels, and decreased cystic follicles. It attenuated PCOS progression by reducing oxidative stress level and suppressing GCs Pyroptosis. At the cellular level, C-PC inhibited DHEA-induced GC Pyroptosis by blocking NLRP3 inflammasome activation and lowering ROS, effects reversed by the NRF2 inhibitor (ML385). Molecular docking analysis and CETSA suggested that C-PC may protect against PCOS by activating the NRF2 pathway or by indirectly binding to the Ser27 site of GSDMD. In addition, C-PC suppressed ROS/p38-MAPK activation induced by DHEA, and p38-MAPK agonists diminished its effect on NLRP3 inflammasome activity and GC Pyroptosis protection.

Conclusion: C-PC exerts a protective effect on GC Pyroptosis through the NRF2/NLRP3/GSDMD and ROS/p-38 MAPK pathways, highlighting its potential to mitigate inflammation and its relevance to reproductive health issues like PCOS.

Keywords

Anti-inflammatory; C-Phycocyanin; Nuclear factor erythroid 2-related factor 2; Polycystic ovary syndrome; Pyroptosis.

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