Multiple genome-wide association study (GWAS) have been carried out recently, that have enhanced our awareness of the genetics underlying Primary Ovarian Insufficiency (POI) and provided the data for Mendelian randomization (MR) study [1,2]. MR relies on genetic variants as exposure instrumental variables (IVs). It is employed to inquire into the link between phenotype exposure and outcome [3]. Two-sample MR analysis allows researchers to evaluate instrument-exposure and instrument-outcome associations in two separate population samples, increasing the applicability and power of the test [4]. In this study, we first extracted valid genetic variants from the published genome-wide association study (GWAS) summary data of 91 inflammatory cytokines in order to investigate their correlations with POI [5].

POI represents a pivotal reproductive ailment, delineated by the premature cessation of ovarian activity prior to the age of 40 [6,7]. Impinging on roughly 1 % of the female populace, POI not only precipitates infertility but also escalates the susceptibility to long-term health detriments such as osteoporosis and cardiovascular disease, consequent to the resultant estrogen scarcity [8,9]. Notwithstanding its prevalent impact, the genesis of POI is inherently intricate and polygenic, entwining genetic predispositions, autoimmune responses, and environmental exposures [10]. The therapeutic landscape for POI currently pivots on ameliorating symptoms, with Hormonal Replacement Therapy (HRT) being the cornerstone for alleviating the negative repercussions of estrogen paucity. Concurrently, Assisted Reproductive Technologies (ART) present a beacon of hope for those yearning for motherhood [11,12]. Albeit, these strategies neither reinstate normal ovarian functionality nor guarantee universal success, underscoring the imperative for groundbreaking therapeutic modalities. The nexus between inflammation and ovarian functionality has been the focal point of burgeoning scrutiny in recent epochs. An array of studies corroborate the association between heightened inflammatory markers and a spectrum of reproductive anomalies, positing inflammation as a pivotal antagonist in the etiology of POI [13,14]. This revelation has catalyzed a paradigm shift towards exploring immunomodulation and the strategic manipulation of inflammatory pathways as avant-garde treatment avenues for POI.

Immunotherapy, predicated on modulating the immune mechanism to combat ailments, emerges as a beacon of promise for POI remediation [15]. Nonetheless, delineating the causative link between these inflammatory entities and POI necessitates further elucidation.

Progress in genome-wide association studies (GWAS) has incrementally improved our knowledge regarding the genetic determinants of POI, providing a solid foundation for subsequent Mendelian Randomization (MR) analyses [16]. MR leverages genetic variants as instrumental variables (IVs) to dissect the nexus between phenotypic exposures and outcomes [17]. Employing two-sample MR analysis, this study endeavors to bridge the knowledge gap by scrutinizing the correlation between 91 inflammatory cytokines, as ascertained from GWAS summary data, and POI, thereby enhancing our understanding of POI's etiology and paving the way for innovative interventions [18].