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<p>Polycystic ovary syndrome (PCOS) is a complex reproductive and metabolic disorder characterized by hyperandrogenism, anovulation, insulin resistance, and chronic low-grade inflammation. The LIF/JAK/STAT3 pathway is very important for coordinating folliculogenesis, endometrial receptivity, and metabolic homeostasis. The LIF–LIFR–gp130–JAK1–STAT3 signaling pathway supports the survival of granulosa cells, follicle recruitment, ovulation, implantation, and mitochondrial function under physiological conditions. In polycystic ovary syndrome (PCOS), hyperandrogenism, hyperinsulinemia, and pro-inflammatory cytokines destabilize the LIFR/gp130 heterodimer, impede LIF and JAK1 signaling, and redirect STAT3 activation towards JAK2-mediated IL-6/leptin-dominated inflammatory pathways. This pathological rewiring promotes hyperandrogenic steroidogenesis by increasing the levels of LHCGR and CYP17A1 and decreasing the levels of FSHR and CYP19A1. It also causes follicular arrest and decreases the ability of the endometrium to accept an embryo by deregulating the LIF/STAT3–MUC1–IGF1 axis. Epigenetic alterations, such as hypomethylation of the first intron of JAK2 and hypermethylation of the SOCS3 promoter, in conjunction with the participation of regulatory non-coding RNAs (miR-181a/b, miR-199a-5p, lncRNA H19, circRNAs), facilitate the amplification of JAK2/STAT3 signaling and the suppression of inhibitory feedback mechanisms. Dysregulated mitochondrial STAT3 leads to impaired oxidative phosphorylation, modified glycolytic pathways, heightened oxidative stress, and worsened insulin resistance. The connections between the MAPK/ERK, PI3K/AKT, TLR4/NF-κB, Wnt/β-catenin, and Hippo/Notch/YAP pathways make this pathological signaling network even stronger. The LIF/JAK/STAT3 axis is a key regulator and a promising target for precision therapies tailored to specific phenotypes in PCOS. Therapeutic strategies, encompassing preclinical JAK inhibitors, metabolic modulators, and clinically validated pathway-directed agents, underscore its potential as a pivotal therapeutic nexus.</p> Graphical Abstract <p></p>

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A Miswired Ovarian Ecosystem: LIF/JAK/STAT3 Distortion in PCOS

  • 期刊论文

  • 发表日期：

    2026年7月22日

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  • Anisha Sharma,
  • Shalini Singh,
  • Ravi Kumar Rajan,
  • Ananya Bhatacharjee,
  • Manodeep Chakraborty

摘要

Polycystic ovary syndrome (PCOS) is a complex reproductive and metabolic disorder characterized by hyperandrogenism, anovulation, insulin resistance, and chronic low-grade inflammation. The LIF/JAK/STAT3 pathway is very important for coordinating folliculogenesis, endometrial receptivity, and metabolic homeostasis. The LIF–LIFR–gp130–JAK1–STAT3 signaling pathway supports the survival of granulosa cells, follicle recruitment, ovulation, implantation, and mitochondrial function under physiological conditions. In polycystic ovary syndrome (PCOS), hyperandrogenism, hyperinsulinemia, and pro-inflammatory cytokines destabilize the LIFR/gp130 heterodimer, impede LIF and JAK1 signaling, and redirect STAT3 activation towards JAK2-mediated IL-6/leptin-dominated inflammatory pathways. This pathological rewiring promotes hyperandrogenic steroidogenesis by increasing the levels of LHCGR and CYP17A1 and decreasing the levels of FSHR and CYP19A1. It also causes follicular arrest and decreases the ability of the endometrium to accept an embryo by deregulating the LIF/STAT3–MUC1–IGF1 axis. Epigenetic alterations, such as hypomethylation of the first intron of JAK2 and hypermethylation of the SOCS3 promoter, in conjunction with the participation of regulatory non-coding RNAs (miR-181a/b, miR-199a-5p, lncRNA H19, circRNAs), facilitate the amplification of JAK2/STAT3 signaling and the suppression of inhibitory feedback mechanisms. Dysregulated mitochondrial STAT3 leads to impaired oxidative phosphorylation, modified glycolytic pathways, heightened oxidative stress, and worsened insulin resistance. The connections between the MAPK/ERK, PI3K/AKT, TLR4/NF-κB, Wnt/β-catenin, and Hippo/Notch/YAP pathways make this pathological signaling network even stronger. The LIF/JAK/STAT3 axis is a key regulator and a promising target for precision therapies tailored to specific phenotypes in PCOS. Therapeutic strategies, encompassing preclinical JAK inhibitors, metabolic modulators, and clinically validated pathway-directed agents, underscore its potential as a pivotal therapeutic nexus.

Graphical Abstract