Role of PI3K gene family as a molecular hub for regulation of growth and immunity: Potential implications for sustainable poultry production

Abstract

Phosphoinositide 3-kinases (PI3Ks) are a conserved family of lipid kinases that link extracellular stimuli to intracellular signaling events for growth, metabolism, reproduction, immunity, and stress adaptation. The PI3K genes in chicken (Gallus gallus) play a vital role in economic traits, such as muscle growth, feed efficiency, production, and disease resistance. The chicken PI3K family consists of 16 members having only catalytic, regulatory, adaptor, and inhibitor sub-units, respectively, with characteristic functions in physiologic processes in PI3K/AKT/mTOR signaling and corresponding networks. Growing evidence suggests role of gene variants in the PI3K gene family (such as SNPs and CNVs), for functional activity in specifying phenotypic diversity in various poultry breeds. The PI3K genes, in addition to basic biology, are promising targets for marker-assisted selection, nutritional regulation, and immunomodulation in poultry production. Opportunities lie in exploring multi-omics methodologies, CRISPR/Cas9-based PI3K editing, and functional validation in avian systems in order to tap PI3K pathways in enhancing productivity, resilience, and sustainability in the poultry sector.

Introduction

The phosphoinositide 3-kinases are an evolutionary conserved family of lipid kinases that are the intersection point of cellular signaling, linking extracellular cues with intracellular processes that govern cell growth, proliferation, survival, and homeostasis (Cuesta et al., 2021). The PI3Ks have been, since their initial characterization, accepted as the main regulators of numerous aspects of physiological and pathological processes in vertebrates, ranging from development and immunity, through reproduction, up to disease development (Lanahan et al., 2022). The PI3K signaling process centers on the phosphorylation of phosphatidylinositol (PIP2) to produce phosphatidylinositol (3,4,5)-trisphosphate (PIP3), the second messenger accountable for attracting PI3K downstream effectors, AKT and mTOR, among others. PI3Ks, via the latter, govern a myriad of biological processes ranging from embryogenesis through metabolic regulation and immune adaptation (Tariq and Luikart, 2021).

In poultry, and especially in the chicken (Gallus gallus), the PI3K family of genes has been a primary determining factor in traits directly impacting productivity, health, and reproduction (Kanakachari et al., 2022). Chickens are among the most economically valuable livestock globally, and their fast growth, feed efficiency, reproductive ability, and disease resistance are fundamental drivers in sustaining the poultry industry (Pius et al., 2021). Molecular network descriptions for the regulation of such traits, therefore, possess scientific as well as applied significance. The PI3K family remains to occupy a position in the regulation of avian skeletal muscle growth, lipidation, immune cellular differentiation, folliculogenesis, angiogenesis, autophagy, and cellular stress responses (Albooshoke and Bakhtiarizadeh, 2019). These various functions exemplify the multifaceted aspect of PI3K signaling and its prospects as a therapeutic target in genetic improvement, nutrient modulation, and disease regulation in poultry production systems.

Structurally, PI3Ks are categorized into three primary classes (I, II, and III), characterized by domain architecture, regulatory sub-units, and modes of activation (Rathinaswamy and Burke, 2020). Class I PI3Ks, made up of catalytic isoforms (p110α, p110β, p110δ, p110γ) and corresponding regulatory sub-units (p85α, p85β, p55γ), are mainly activated by G-protein–coupled receptors and receptor tyrosine kinases and are significantly involved in immunity, growth, and metabolism (Nürnberg and Beer-Hammer, 2019). Class II PI3Ks (PIK3C2A, PIK3C2B, and PIK3C2G), fewer in characterization, are involved in insulin signaling, endocytosis, and vesicular trafficking (Margaria et al., 2019). The only Class III PI3K, PIK3C3 (Vps34), is indispensable in endosomal trafficking as well as in autophagy. Along with the catalytic sub-units, regulatory modules PIK3AP1, PIK3IP1, PIK3R4, PIK3R5, and PIK3R6 work toward maintaining specific activity in PI3 (Rebollo Gomez, 2020).

The recent genomic and functional research has shown that PI3K genes in chicken are remarkably conserved but have distinctive patterns of adaptation that characterize birds compared to mammals (Albooshoke and Bakhtiarizadeh, 2019). For example, patterns of differential expression of PI3K isoforms in tissues, including liver, muscle, ovary, and immune organs, point out their specialized functions in avian physiology (Tesseraud et al., 2006). Additionally, emerging evidence indicates that spontaneous genetic variation, including single nucleotide polymorphisms (SNPs) and gene duplications within PI3K family genes, gives rise to variations in growth, feed efficiency, immune function, and reproductive ability among chicken lines and breeds. Such evidence points towards the need to integrate genomics, transcriptomics, and functional assays to disentangle the entire range of PI3K gene family activities in birds (Wang and Ibeagha-Awemu, 2021).

Although comprehensive PI3K biology was developed from mammalian studies, avian-specific functional studies are relatively rare, with a very small number of studies focusing on CRISPR/Cas9-mediated editing or multi-omics studies in chicken. The term “multi-omics” refers to the integrated use of genomics, transcription, proteomics, and metabolomics to investigate PI3K gene functions and their regulatory networks in chickens. Such virtual absence indicates a need for the generation of models specific to chicken to confirm functions routinely assumed from mammals, since chicken possess characteristic physiology such as relative insulin resistance, rank follicle selection, and enhanced sensitivity to environmental stress (Scanes et al., 2022). Improving PI3K studies in chicken is then not only a subject of theoretical interest but also of practical relevance in the poultry industry, where molecular application is a future possibility for increasing feed efficiency, increasing vaccine response, prolonging reproductive lifespan, and assisting breeding for climatic resilience. Emphasizing both the gap in our present avian studies and the possibility of practical translation, the present review attempts a forward-looking synthesis bridging molecular mechanism with applied poultry production (Han et al., 2024).

This study synthesizes our current knowledge on the genomics organization, classification, and physiological role of the PI3K gene family in chicken. This study outlines the physiological functions of PI3Ks in major physiological processes such as growth, metabolism, immunity, and reproduction, as well as reviews their possible role in poultry health and production. Through the inclusion of evidence on genomics, molecular biology, and application in applied poultry science, this manuscript aims to provide a general understanding of the PI3K gene family and outline future research and potential implications for PI3K genes in poultry production.

Members of the PI3K gene family

The PI3K family of chicken consists of 16 members that are broadly placed under the catalytic sub-units, regulatory sub-units, and adaptor or inhibitor proteins and are divided into three general classes (I-III) (Höland, 2012). Each of the classes contributes toward unique but overlapping aspects of cell signaling and allows coordination of growth, metabolism, immunity, and reproduction of domestic chicken (Albooshoke and Bakhtiarizadeh, 2019).

The Class I PI3Ks are the most characterized and are further divided into Class IA (PIK3CA, PIK3CB, and PIK3CD with regulatory sub-units PIK3R1, PIK3R2, and PIK3R3) and Class IB (PIK3CG with regulators PIK3R5 and PIK3R6) subgroups (Rathinaswamy and Burke, 2020). The catalytic sub-units, collectively referred as p110 isoforms, phosphorylate membrane phosphoinositides to produce PIP3 and activate downstream effectors like AKT and mTOR (Fox et al., 2020). PIK3CB (p110β) mediate this function by regulating insulin-mediated glucose uptake, lipid metabolism, and nutrient use efficiency (Kwon and Pessin, 2020). Immunity-associated isoforms PIK3CD (p110δ) and PIK3CG (p110γ) are highly expressed in leukocytes. PIK3CD is crucial for B- and T-cell development and antibody synthesis and cell proliferation of leukocytes, and PIK3CG regulates chemo-taxis and inflammatory processes using GPCR (G-Protein Coupled Receptor) signaling and play a significant role in resistance and immunity of poultry (Kianpoor et al., 2025).

Class II PI3Ks, (PIK3C2A, PIK3C2B, and PIK3C2G), are monomeric enzymes that are defined by their C-terminal C2 domain. While not so well characterized as their Class I counterparts, they are known to play a role in endocytosis, vesicle movement, and metabolism control (Margaria et al., 2019). PIK3C2A is known to control insulin signaling and glucose uptake by regulating GLUT4 translocation and is involved in renal development and ciliogenesis (Nakamura et al., 2022). PIK3C2B is involved in vesicle movement dynamics and intracellular trafficking of proteins and membrane remodeling, processes vital for gut absorption of nutrients and movement within cellular compartments (Margaria et al., 2019). The PIK3C2G is comparatively less defined but is known to be associated with mammalian tumour suppression and can play a role in cell proliferation, immune and reproductive functions (Kianpoor et al., 2025).

PI3K Class III includes only one highly conserved gene, PIK3C3 (also referred to as Vps34), which phosphorylates phosphatidylinositol to synthesize PI3P. This is a key lipid signaling molecule essential for initiating autophagy, endocytic trafficking, and cellular homeostasis (Bilanges et al., 2019). PIK3C3 is essential to acquire and maintain energy homeostasis under condition challenging conditions of poor nutrition, compromised immune status and environmental stress. Its close connection with the regulatory sub-unit PIK3R4 (p150) highlights its special role in autophagy and vesicle dynamics (Chaudhary and Mishra, 2024).

Class I PI3K regulatory sub-units PIK3R1 (p85α), PIK3R2 (p85β), and PIK3R3 (p55γ) play a crucial role in the stabilization and activation of catalytic sub-units (Rathinaswamy and Burke, 2020). PIK3R1 is the highly expressed and ubiquitous regulatory isoform linking receptor tyrosine kinase and PI3K activation and balancing signaling within reproductive and metabolic tissues (Tsay and Wang, 2023). PIK3R2 and PIK3R3 fine-tune tissue-specific signaling and play a role in nutrient sensing, growth regulation, and cell differentiation. Lastly, Class IB regulatory proteins PIK3R5 (p101) and PIK3R6 (p87) are crucial members for activation of PIK3CG by immune cell GPCRs and play a direct role in chemo-taxis and leukocyte activation (Nürnberg and Beer-Hammer, 2019).

In addition to catalytic and regulatory sub-units, two other proteins (PIK3AP1 and PIK3IP1) have special functions in the modulation of PI3K signaling. PIK3AP1 (BCAP) is an adaptor protein signaling from the B-cell receptor (BCR) and Toll-like receptor (TLR) to the PI3K signaling system. PIK3AP1 facilitates survival of immune cells and cross-talk of innate and adaptive immunity (Ni et al., 2012). PIK3IP1, on the other hand, acts as a negative regulator through direct interaction of the catalytic sub-units and suppression of PI3K function. Such suppressive regulation inhibits the uncontrollable growth of cells, tumorigenicity, and metabolic disorder (He et al., 2008). PIK3IP1 was previously identified as being down regulated in chicken for fast growth and lipid accumulation and suggests a productivity-metabolic health trade-off (Jia et al., 2024)

Methodology

A systematic search strategy was employed to identify literature related to the PI3K gene family in poultry. Scientific publications from 2000 to 2025 were searched using the different search engines mainly Google Scholar and PubMed. Keywords and Boolean operators applied to retrieve the articles included “PI3K gene family in chicken,” “PI3K signaling,” “PI3K/AKT/mTOR pathway,” “growth and metabolism,” “immune response,” “folliculogenesis,” “multi-omics,” and “CRISPR/Cas9 editing in poultry.” Reference lists of selected articles were further screened to capture other relevant studies. Inclusion criteria consisted of (i) peer-reviewed publications, (ii) studies involving poultry species or comparative animal models, where avian evidence is limited, and (iii) articles dealing with genomic, molecular, or physiological functions of PI3K genes. Review papers, original research articles, and recent preprints whose data had been verified were eligible. Articles that were not relevant at a molecular level to PI3K signaling, non-avian studies without any comparative justification, and reports whose full text was inaccessible were excluded. A total of 145 studies were screened, and those that met the set criteria totaled 82 and were thus included and synthesized in this review.

Functional roles of the PI3K gene family in chicken

Control of cell division and growth

Out of the four primary biological functions of the PI3K gene family, one is the proliferation and growth of cells. PI3K signaling, through priming cells and setting them ready and responsive to inputs from the outside, such as growth factors, cytokines, and hormones, to stimulate embryonic growth, post-hatch growth, and tissue repair (Kanakachari et al., 2022). Central to the entire mechanism is the PI3K/AKT/mTOR signaling pathway resulting from the phosphorylation of phosphatidylinositol (4,5)bis-phosphate (PIP2) through PI (Fig. 1; Tariq and Luikart, 2021). This second messenger phospholipid transports AKT (protein kinase B) to the membrane, where it's phosphorylation occurs resulting in activation of protein synthesis, metabolic, and cell cycle entry effector (Neri et al., 2002). Class I catalytic isoforms of PI3K, particularly PIK3CA (p110α) and PIK3CB (p110β), are prominently featured in muscle and liver tissues of chicken and are accountable for accretion of proteins, myoblast proliferation, and skeletal muscle hypertrophy (Fig. 1; Albooshoke and Bakhtiarizadeh, 2019). Regulator sub-units (PIK3R1, PIK3R2, and PIK3R3) of these catalytic proteins stabilize these proteins and ensure receptor specificity and anchor receptor tyrosine kinases and growth factor receptors for PI3K activation (Rathinaswamy and Burke, 2020).

Fig. 1.

PI3K/AKT/mTOR signaling governs nutrient metabolism and cell growth in chicken. Growth-factor binding activates PI3K, which then subsequently phosphorylates AKT, resulting in the activation of mTOR, which increases protein synthesis associated with muscle development and feed efficiency. (Figure generated by using BioRender).

Immune-related isoforms such as PIK3CD (p110δ) and PIK3CG (p110γ), although primarily involved in leukocyte signaling, also contribute to proliferation by promoting clonal expansion of B and T cells, thereby supporting the rapid development of immune competence in young chicks (Okkenhaug and Vanhaesebroeck, 2003). Beyond Class I, Class II PI3Ks (PIK3C2A and PIK3C2B) indirectly regulate proliferation by modulating vesicle trafficking and endocytosis, processes essential for nutrient uptake and receptor recycling (Baines et al., 2022). PIK3C3 (Vps34), the sole Class III isoform, plays a supporting role through autophagy, ensuring that dividing cells recycle nutrients efficiently and maintain energy balance during metabolic stress (Yuan et al., 2013). Together, these genes integrate nutritional, hormonal, and environmental signals into coherent cellular responses, enabling birds to sustain rapid growth rates under intensive production systems. Dysregulation of this pathway, however, may lead to uncontrolled growth, developmental abnormalities, or metabolic imbalances, highlighting the importance of precise PI3K regulation for poultry health and productivity (Al-Surrayai and Al-Khalaifah, 2022; Albooshoke and Bakhtiarizadeh, 2019; Shen and Gleghorn, 2025).

Mammalian studies have outlined comprehensive PI3K-controlled growth mechanisms, but avian-specific functional verification is limited, and it is therefore necessary for specific studies to establish an answer to the question of whether corresponding regulatory mechanisms exist in chicken (Table 1, Table 2).

Table 1.

Summary of PI3K isoforms in chickens: functions, mammalian comparison, and potential poultry applications.

Isoform	Primary Function in Chickens	Mammalian Comparison	Potential Applications
PIK3CA (p110α)	Muscle growth, protein synthesis, lipid metabolism	Conserved role in growth and metabolism	Genetic marker for broiler muscle accretion and feed efficiency
PIK3CB (p110β)	Insulin signaling, glucose uptake, metabolic balance	Similar insulin/glucose regulation in mammals	Precision feeding and reducing metabolic disorders
PIK3CD (p110δ)	B- and T-cell proliferation, antibody production	Well studied in mammalian adaptive immunity	Improve vaccine responses, reduce antibiotic reliance
PIK3CG (p110γ)	GPCR-mediated chemotaxis, innate immune response	Conserved immune signaling role	Enhance resistance to infections and improve flock health
PIK3C2A	Insulin signaling, GLUT4 trafficking, vesicle transport	Similar role in mammals, less characterized	Target for nutrient absorption and feed efficiency
PIK3C2B	Vesicular trafficking, intracellular protein movement	Supports vesicle recycling in mammals	Improve gut absorption and metabolic agility
PIK3C2G	Potential tumor suppression, cell growth	Linked to tumor regulation in mammals	Marker for disease resistance and growth balance
PIK3C3 (Vps34)	Autophagy, endocytosis, stress adaptation	Strongly conserved in mammals	Enhance resilience to heat and nutrient stress
PIK3R1 (p85α)	Regulatory, stabilizes catalytic subunits	Conserved across vertebrates	Supports metabolic regulation and reproductive signaling
PIK3R2 (p85β)	Fine-tunes tissue-specific PI3K activity	Similar modulatory role in mammals	Optimize nutrient sensing in production systems
PIK3R3 (p55γ)	Tissue-specific regulation, cell differentiation	Also regulatory in mammals	Potential marker for growth–reproduction trade-offs
PIK3R4 (p150)	Partner of Vps34, autophagy regulation	Conserved autophagy regulator	Improve stress resilience and survival under heat/feed restriction
PIK3R5 (p101)	Activates PIK3CG in immune cells	Same role in mammalian immune signaling	Enhance innate immune defense in poultry
PIK3R6 (p87)	Co-regulates PIK3CG signaling	Shared with mammals	Improve vaccine responsiveness
PIK3AP1 (BCAP)	Links BCR/TLR to PI3K, immune modulation	Conserved adaptor function	Strengthen adaptive and innate immune crosstalk
PIK3IP1	Negative regulator, tumor suppression	Acts as molecular brake in mammals	Balance rapid growth with metabolic health, reduce tumor risk

Table 2.

Members of the chicken PI3K gene family, their functions, chromosomal distribution, and protein characteristics.

Gene	Subunit Type / Class	Primary Function in Chicken	Location	Molecular Weight (kDa)	No. of Amino Acids
PIK3CA	Catalytic (Class IA, p110α)	Cell growth, skeletal muscle hypertrophy, lipid metabolism	Chr 9	124288.1	1068
PIK3CB	Catalytic (Class IA, p110β)	Insulin signaling, glucose uptake, metabolic homeostasis	Chr 9	122018.3	1066
PIK3CD	Catalytic (Class IA, p110δ)	Immune cell signaling (B- and T-cell proliferation, antibody production)	Chr 21	120246	1046
PIK3CG	Catalytic (Class IB, p110γ)	GPCR-mediated chemotaxis, inflammation, innate immunity	Chr 1	128012.1	1106
PIK3C2A	Catalytic (Class II)	Insulin signaling, GLUT4 trafficking, vesicle transport	Chr 5	191769.1	1702
PIK3C2B	Catalytic (Class II)	Cell proliferation, survival, intracellular trafficking	Chr 26	183891.2	1628
PIK3C2G	Catalytic (Class II)	Cell growth, vesicle trafficking, potential tumor suppression	Chr 1	170463.9	1494
PIK3C3 (Vps34)	Catalytic (Class III)	Autophagy initiation, endocytosis, cellular homeostasis	Chr Z	105933.6	928
PIK3R1	Regulatory (Class IA, p85α)	Stabilizes catalytic subunits, growth factor signaling	Chr Z	83800.37	724
PIK3R2	Regulatory (Class IA, p85β)	Modulates Class I PI3K specificity and activity	Chr 28	83493.83	731
PIK3R3	Regulatory (Class IA, p55γ)	Tissue-specific regulation of PI3K signaling	Chr 8	83322.36	733
PIK3R4	Regulatory (Class III, p150)	Autophagy regulation (partner of PIK3C3)	Chr 2	153499	1361
PIK3R5	Regulatory (Class IB, p101)	Activates PIK3CG in immune cells via GPCRs	Chr 18	98544.52	882
PIK3R6	Regulatory (Class IB, p87)	Enhances GPCR-mediated immune signaling with PIK3CG	Chr 18	85395.35	765
PIK3AP1 (BCAP)	Adaptor Protein	Links BCR/TLR signaling to PI3K pathway; immune modulation	Chr 6	91152.45	809
PIK3IP1	Inhibitory Protein	Suppresses PI3K catalytic subunits; tumor suppression	Chr 15	27677.56	262

Incorporating nutrient sensing and feed efficiency

One of the major role of the PI3K gene family in chicken is the coordination of nutrient sensing and growth efficiency, a trait of great economic significance in broiler and layer industries (Contriciani et al., 2024). Feed is the main cost factor in broiler and layer operations, and hence the ability of birds to convert feed into body mass is indirectly related to profitability. PI3K/AKT/mTOR signaling is a central nutrient sensor that converts dietary inputs like glucose, amino acids, fatty acids, and insulin into intracellular anabolic signals (Koundouros and Blenis, 2022). After feeding, insulin and insulin-like growth factors (IGFs) activate Class I catalytic isoforms (PIK3CA and PIK3CB), which phosphorylate membrane lipids and produce PIP3 (Molinaro, 2020). This activates AKT, a metabolizing switch that promotes glucose uptake by inducing GLUT4 translocation and elevates glycogen storage and drives protein synthesis by activating mTORC1 (Beg et al., 2017). These actions are of vital interest where nutrient assimilation makes a direct contribution to body weight and muscle accretion and are highly significant in metabolically active tissues like liver, skeletal muscle, and gastrointestinal tract (Omar et al., 2022, Saha and Pathak, 2021).

The regulatory sub-units (PIK3R1, PIK3R2, and PIK3R3) adjust the strength and duration of PI3K activity and achieve optimal partitioning of nutrient-driven growth versus cellular homeostasis. During periods of excess nutrients, PI3K signaling enhances quick anabolic growth and a better feed conversion ratio (FCR), whereas under nutrient-limited situations, the Class III isoform PIK3C3 (Vps34) is crucial by triggering autophagy and activating intracellular nutrient stores to maintain growth (Yuan et al., 2013). Correspondingly, Class II PI3Ks (PIK3C2A and PIK3C2B) are involved in nutrient receptor and transporter intracellular trafficking and indirectly contribute to increased feed efficiency through promotion of absorption and metabolic agility (Margaria et al., 2019). A third layer of regulation is introduced from PIK3IP1, a PI3K activity negative modulator, in an attempt to prevent over activation of the pathway and preserve metabolic stability (Hopkins et al., 2020). Surprisingly, broiler strains bearing better feed efficiency tend to show PIK3IP1 down regulation and up regulation of PIK3CA, PIK3CB, and PIK3R1 and show a genetic association of nutrient efficiency to PI3K signaling (Albooshoke and Bakhtiarizadeh, 2019). Together, the PI3K gene family serves as a molecular hub connecting the diet and growth and enables chickens to partition nutrients favourable to muscle tissue while keeping fat deposition low and hence improving both producer economics and carcass quality (Lee, 2012).

For the poultry sector, nutrient sensing via PI3K holds the key to maximizing feed conversion ratio, the most crucial economic trait in broilers (Perry, 2023). Unlike mammals, chicken possess typical metabolic regulation with relative insulin-resistance, such that PI3K activity remains a promising molecular entity for precision feeding. Straight functional studies from PI3K variants to poultry feed efficiency are limited and await experimental verification (Lee, 2012).

Modulation of immature immune cell maturation and activity

The PI3K gene family is the key to the development, activation, and functioning of the avian immune system and regulates both innate and adaptive immunity (Luo et al., 2022). Among the catalytic isoforms, PIK3CD (p110δ) and PIK3CG (p110γ) are widely expressed within leukocytes and regulate downstream signaling of the B-cell receptor (BCR), T-cell receptor (TCR), cytokine receptors, and G-protein coupled receptors (GPCRs) (Wu, 2022). PIK3CD is particularly crucial for B- and T-lymphocyte proliferation and differentiation and mediates antibody output and establishment of adaptive immunity (Nguyen, 2021). PIK3CG, when activated by GPCRs, regulates neutrophil and macrophage chemotaxis and migration and mediates effective innate immune responses and inflammation. Deficiencies of both isoforms are related to reduced immune competence and impaired vaccine response and susceptibility of birds to infections (Laganà et al., 2021).

Class I PI3K regulatory sub-units (PIK3R1, PIK3R2, and PIK3R3) set out on their mission in immune-cell signaling through the maintenance of the catalytic sub-units (Kim et al., 2024). Class IB are also essential regulator partners PIK3R5 (p101) and PIK3R6 (p87), necessary co-factors for PIK3CG and stimulators of its activation in neutrophil migration and cytokines responses (Lanahan et al., 2022). Except for Class I, Class III PI3K (PIK3C3/Vps34) itself is involved in the regulation of autophagy in immune system cells and is critical for antigen presentation, microbe and virus clearance, as well as numerous intracellular parasites, and T-cell homeostasis (Caux et al., 2022). This is complemented by its corresponding regulatory PIK3R4 (p150), through which proper vesicular trafficking and survival of stress-exposed immune cells is ensured (Chen, 2025).

Adapter and inhibitory proteins possess distinctive immune functions. PIK3AP1 (BCAP) is an important adaptor linking activation of BCR and TLR to activation of PI3K and thereby connects innate and adaptive immunity (Lagos et al., 2024). PIK3IP1 acts as a negative regulator in balancing the proliferation of immune cells and forestalling inflammatory or autoimmune responses out of control. Collectively these genes represent a finely regulated immune-regulatory system in chicken that balances activation and suppression and orchestrates efficient defense against pathogens while favoring immune homeostasis. The role of PI3K genes is of crucial significance for poultry farming due to the supreme importance of disease resistance and immune responses against vaccines in determining flock health and productive performance (Xie et al., 2022).

Application of PI3K isoforms such as PIK3CD and PIK3CG can strengthen poultry vaccine responses and help achieve a transition from antibiotic use, a major sustainability goal (Al-Khalaifah and Uddin, 2022; Kim and Lillehoj, 2019). Mammalian studies already establish PI3K's role in adaptive immunity, but avian-specific models are then required to translate such findings applied to flock health improvement and disease resistance breeding (Tesseraud et al., 2021).

Reproduction and follicular growth

The PI3K gene family is involved in bird reproductive physiology regulation, particularly in the selection and growth of ovarian follicles, oocyte maturation, and maintenance of reproduction efficiency (Fig. 2: Zhao et al., 2023). Folliculogenesis in birds is a controlled process where a small quantity of follicles is selected to mature and ovulate, and the vast majority is induced to experience atresia. It is controlled mainly through the PI3K/AKT/mTOR signal transduction pathway dominating granulosa proliferation, survival, and steroidogenic activity (Peng et al., 2025). Activation of Class I catalytic isoforms, mainly PIK3CA and PIK3CB, activates granulosa growth and proliferation, follicle survival and estradiol production, thereby facilitating follicular selection and growth (Fig. 2). At the same time, PI3K/AKT activity inhibits apoptosis through inhibition of pro-apoptotic proteins such as BAD and caspases in order to prevent atresia for lead follicles and bring them to ovulation (Zhao et al., 2021).

Fig. 2.

PI3K/AKT, mTOR, and FOXO3A interactions in the regulation of reproductive function and follicular development. FSH, LH, HGF, and c-Kit signaling activate PI3K to promote proliferation of granulosa cells and oocyte maturation, while inhibiting follicular atresia, maintaining the potential for reproductive efficiency. (Figure generated by using BioRender).

Catalytic immune-related isoforms PIK3CD and PIK3CG, although mostly studied in leukocytes, are involved in reproductive regulation through follicular growth and ovulation through ovarian immune response and environment effects (Obeagu and Obeagu, 2025). Class II PI3Ks (PIK3C2A and PIK3C2B) possess a complementary role in vesicular trafficking, receptor recycling, and glucose uptake in ovarian cells for satisfying follicular growth's energetic and metabolic requirements (Zhang et al., 2023). PIK3C3 (Vps34) and its accompanying PIK3R4 (p150) control autophagy in granulosa cells, a reaction needed to achieve cellular quality control and nutrient recycling that affects follicle health and survival (Kumariya et al., 2021).

Regulatory and adaptor proteins allow additional levels of regulation. PIK3R1 and PIK3R2 deliver receptor-mediated activation of PI3K signaling upon stimulation with gonadotrophins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Deng et al., 2021). PIK3AP1 and PIK3IP1 have indirect roles; the former in linking immune–metabolic messages to ovarian function and the latter in breaking PI3K signaling to suppress aberrant follicular growth (Rajareddy, 2007). Interestingly, reduced PIK3IP1 expression supports follicle survival in pig, suggesting it plays a key role in follicle selection between atresia (Terenina et al., 2017).

As a family, PI3K genes control a number of cellular processes, including granulosa cell proliferation, steroidogenesis, inhibition of autophagy, and inhibition of apoptosis, that collectively foster successful folliculogenesis and reproductive performance. By controlling ovarian function, these genes fundamentally impact might impact rates of egg production, reproductive life span, and overall commercial production in poultry systems (Zhu et al., 2021).

PI3K-regulated folliculogenesis in chicken has a direct impact on reproduction and fertility in the breeder flock, serving as a selection criterion of interest. Mammals exhibit cyclical ovulation, and birds exhibit hierarchic selection of follicles and may exhibit PI3K-characteristic adaptations. Functional studies in chickens are not well established, and CRISPR/Cas9 or multi-omics integrations may reveal new regulations to extend laying cycles and promote reproduction efficiency (Wadood and Zhang, 2024).

Angiogenesis and tissue repair

PI3K family genes have a central role to play in angiogenesis and wound healing, which is a process indispensable to embryonic development, organ maturation, and tissue homeostasis in birds (Nawaz et al., 2023). Angiogenesis, or the development of new blood capillaries from existing vasculature, is especially critical during growth spurts in broilers and follicular development in layers, wherein ovarian tissues need higher vascularization to provide steroidogenesis and yolk material deposition (Machura and Hrabia, 2024). PI3K signaling controls angiogenesis mainly via the PI3K/AKT/mTOR pathway that phosphorylates downstream targets such as endothelial nitric oxide syntheses (eNOS), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1 alpha (HIF-1α). Such proteins bring about proliferation and migration of endothelial cells and tube formation that eventually generate new blood capillaries (Fig. 3; Li et al., 2023).

Fig. 3.

Activation of PI3K/AKT/mTOR promotes angiogenesis through upregulation of eNOS, VEGF, and HIF-1α. In poultry, this pathway enhances blood vessel formation and thus muscle oxygenation and tissue repair, contributing to an improvement in growth and resilience under stress challenges. (Figure created by BioRender.).

Of the catalytic isoforms, PIK3CA and PIK3CB play a key role in vascular growth through the mediation of VEGF-induced endothelial reactions, whereas PIK3CD and PIK3CG control immune cell recruitment to damaged locations and facilitate a healing environment (Lanahan et al., 2022). Class II PI3Ks (PIK3C2A and PIK3C2B) are a big help in managing vesicle trafficking and membrane re-modelling, both of which are essential to migration and stability of adherence junctions in endothelial cells (Anquetil et al., 2021). While this goes on, PIK3C3 (Vps34) and regulatory partner PIK3R4 (p150) aid autophagy and vesicle trafficking to keep endothelial and tissue cells in a state of energy equilibrium in cases of oxygen deficiency or tissue damage (Shen and Gleghorn, 2025).

Regulatory proteins also act on vascular dynamics. The PIK3R1 and PIK3R2 regulate receptor-driven angiogenic signaling upon growth factor stimulation by stabilizing a family of catalytic sub-units (Viglietto et al., 2011). For immune-mediated tissue repair, PIK3AP1 (BCAP) connects Toll-like receptor (TLR) inputs to PI3K activation to aid in inflammatory resolution and tissue re-modelling. By opposing excess angiogenic stimulation, PIK3IP1 prevents an imbalance between vessel growth and tissue integrity (Troutman et al., 2012).

In domestic poultry, angiogenesis is particularly involved in embryonic development, in which sufficient vascularization of the chorioallantoic membrane and yolk sac allows oxygen and nutrient transportation to the growing embryo (McNeil, 2018). Furthermore, muscle angiogenesis contributes to improved meat quality by ensuring a sufficient supply of oxygen and metabolic backup during muscle hypertrophy. Reproductive physiology involves enhanced ovarian follicle blood supply, securing sufficient yolk deposition and maturation of follicles (Das et al., 2023). When tissue repair takes place, angiogenesis mediated by PI3K ensures rapid healing and return to normalcy after infection or stress. Overall, this PI3K family of genes provides a coherent molecular blueprint for angiogenesis and tissue repair, connecting growth, reproductive effectiveness, and resilience in birds (Nawaz et al., 2023).

Angiogenic enhancement supports muscle quality, yolk formation, and embryo viability, for which PI3K signaling offers a putative locus for a poultry industry intervention (Kanakachari et al., 2022). Angiogenesis in mammals is a well-documented phenomenon, although avian-specific functional studies are few, thereby providing possibilities for PI3K-dependent vascular accommodation research in high-output and high-growth layer broilers.

Skeletal muscle growth

Muscle development is a pillar of poultry production due to muscle tissue being a chief constituent of meat yield in broilers. Myogenesis regulation, muscle hypertrophy, and post-hatch muscle growth involve the PI3K gene family, integrating growth signals coming into cells with intracellular anabolic networks (Kanakachari et al., 2022). A noteworthy pathway in muscle development is the PI3K/AKT/mTOR system due to its regulation of proliferation and differentiation of myoblasts and protein synthesis (Ling et al., 2021). Through activation by IGFs or growth hormone, Class I PI3Ks (particularly PIK3CA and PIK3CB) phosphorylate membrane lipids to produce PIP3, upon which AKT is recruited and activated. Phospho-AKT stimulates protein synthesis via mTORC1, accelerates ribosome bio-genesis, and suppresses catabolic controllers such as FOXO transcription factors to cause protein breakdown decrease (Fig. 4; He et al., 2021). PIK3CD (p110δ) and PIK3CG (p110γ) are class I PI3K catalytic isoforms predominantly associated with immune function in leukocytes (Lanahan et al., 2022). Class II isoforms (PIK3C2A and PIK3C2B) contribute to myogenesis indirectly due to control of vesicular movement and glucose uptake to supply energy substrates to fast-proliferating muscle fibres. PIK3C3 (Vps34) makes a further contribution to muscle maintenance in the skeletomuscular system due to control of autophagy to prepare amino acids and energy during a phase of nutrient deficiency and muscle homeostasis and adaptability to feed restriction (Xia et al., 2021). Regulatory units PIK3R1, PIK3R2, and PIK3R3 facilitate maximal activation of catalytic isoforms upon muscle growth factor stimulation, while PIK3R4 (p150) associates with PIK3C3 to regulate autophagic control of muscle cells (Tsay and Wang, 2023). PIK3AP1 (BCAP) and PIK3IP1 regulate muscle growth additionally via immune-metabolic crosstalk: BCAP induces PI3K activation upon immune-mediated muscle repair, while PIK3IP1 has an antagonist role in regulating excessive growth signalization. Interestingly, low PIK3IP1 expressions were correlated with fast muscle accretion in broilers, signifying its function in regulating muscle growth against metabolic cost (Albooshoke and Bakhtiarizadeh, 2019).

Fig. 4.

Activation of mTORC1 through PI3K/AKT in chicken cells; promote protein synthesis, lipid metabolism, and cytoskeletal organization. The pathway links nutrient sensing to cellular growth and affect economically important traits such as muscle yield and feed conversion. (Figure generated by BioRender).

In poultry meat production, PI3K activity is directly related to feed conversion ratio (FCR), breast muscle yield, and growth rate, high-economic traits (Akuru, 2022). Increased PI3K signaling contributes to fast myofiber hypertrophy, hence increased body weight and meat yield, while moderate autophagy provides long-term muscle quality and stress resilience. Therefore, the PI3K family is a principal molecular determinant of skeletal muscle growth, connecting genome regulation to production traits in poultry (Fig. 4; Xu and Velleman, 2023).

PI3K-controlled myogenesis in broilers maintains body weight gain and carcass quality and is among the most promising molecular networks for avian improvement. Comparative analyses indicate analogous networks in mammals, although chickens might represent a singular case for very high growth rates and uneven metabolic trade-offs. Experimental verification in avian models must occur in a bid to pinpoint causal variants for inclusion in selection schemes (Garland Jr et al., 2022).

Response to stresses and cellular survival

PI3K family genes are instrumental in regulating cellular response to stress and survival mechanisms, enabling chickens to respond to environmental, nutritional, and pathogenic challenges common in intensive production systems (Albooshoke and Bakhtiarizadeh, 2019). Heat stress, starvation, anoxia, and infections can disrupt cellular homeostasis leading to oxidative damage, apoptosis, or metabolic perturbation. Cells respond to these destructive effects through the PI3K/AKT signaling pathway to trigger pro-survival protein cascades (Gouda et al., 2024; Pungsrinont et al., 2021). Catalytic Class I isoforms (PIK3CA and PIK3CB) control this process by generating PIP3 and activating phosphorylation of AKT that inactivates pro-apoptotic proteins such as BAD, GSK-3β, and caspases while activating survival-promoting transcription factors such as NF-κB and CREB. Dual control prevents apoptosis and stimulates stress response genes' transcription to achieve cell survival (Duronio, 2008).

Vps34 (PIK3C3) is a solitary Class III PI3K and plays a central role in adaptation to stress through autophagy initiation. Autophagy possesses an internal recycling system that provides amino acids and energy while removing damaged organelles upon nutrient starvation or oxidative stress and works to maintain cellular integrity (Yuan et al., 2013). Its regulatory part, PIK3R4 (p150), enhances this activity through stabilization of the Vps34 complex to obtain optimal autophagic flux. Its Class II counterparts (PIK3C2A and PIK3C2B) undertake vesicle transport and membrane repair that is valuable under oxidative and mechanical stress (Margaria et al., 2019). Activation is optimal for immune cell survival and cytokines communication in response to infection, but can cause immunopathology upon chronic stress. Additionally, adaptor and inhibitory proteins tightly control stress signaling outputs: PIK3AP1 (BCAP) supports PI3K activation in response to stress in immune cells, but PIK3IP1 avoids hyper activation of the pathway and regulates a survival versus regulated apoptosis balance (Murter and Kane, 2020).

In poultry, where heat stress and nutrient deprivation/excess are two major production constraints, PI3K-mediated processes have been directly involved in maintaining intestinal integrity, muscle function in the skeleton, and immune function (Kanakachari et al., 2022). Through enabling cells to adapt to fluctuating supplies of energy, oxidative states, and inflammatory settings, the PI3K family of genes safeguards global bird health, production, and survival within intense agriculture (Al-Khalaifah and Uddin, 2022; Chaudhary and Mishra, 2024).

Under conditions of heat stress, nutrient limitation, and infections, PI3K-regulated stress tolerance provides a route towards producing climate-resilient birds. Though PI3K's orchestrating function in cellular survival in mammals is portrayed, such evidence in birds is absent, particularly for production-relevant stresses such as heat stress (Surai and Surai, 2024). A key area for future exploration remains the practical application of such findings towards useful resilience traits for the poultry industry.

Insulin signal trafficking and glucose balance

The PI3K family of genes is a linchpin of glucose regulation and insulin signaling in chickens and has a direct impact on feed efficiency, growth performance, and metabolic stability (Lv et al., 2023). Being naturally less responsive to insulin compared to mammals, chickens still have the PI3K/AKT pathway act as the primary mediator of insulin action in birds (Dupont et al., 2009). The binding between insulin and the insulin receptor, Class I catalytic isoforms (PIK3CA and PIK3CB), becomes recruited and active due to interactions with regulatory sub-units (PIK3R1, PIK3R2, and PIK3R3) (Sohn, 2022). Phosphorylation PI3K produces PIP3 within the plasma membrane, which in turn recruits AKT for phosphorylation. Once phosphorylated, AKT is activated to phosphorylate numerous downstream targets that overall increase glucose use and storage (Kane and Weiss, 2003).

One of the key consequences of PI3K signaling is the activation of GLUT4 translocation to the plasma membrane in muscle and adipose tissues to raise glucose uptake. It is pivotal to muscle accretion, energy provision, and fat metabolism in poultry (Ramachandran and Saravanan, 2015). Furthermore, PI3K/AKT signaling stimulates glycogen synthesis by suppressing glycogen synthase kinase-3β (GSK-3β) activity to store glucose efficiently in muscle and liver during excess nutrients. It also controls lipid metabolism to balance glucose–lipid partitioning and avert metabolic diseases like fatty liver that occur widely in laying hens (Pan and Valapala, 2022).

Additional family members also help regulate glucose. Class II PI3Ks (PIK3C2A and PIK3C2B) have secondary roles in vesicular trafficking and receptor recycling that are crucial to sustaining transporter function and insulin receptor availability (Margaria et al., 2019). PIK3C3 (Vps34) has an indirect role regulating glucose metabolism due to its autophagic function to mobilize intracellular nutrient stores in fasting or energy stress (Yuan et al., 2013). Inhibitory proteins such as PIK3IP1 function as molecular brakes that restrict PI3K activation, thereby preventing metabolic overload, whereas adaptor proteins like PIK3AP1 (BCAP) integrate immune and metabolic signals, modulating glucose homeostasis during stress or infection (Benjamin and Kane, 2020).

Overall, PI3K gene family regulates a fluctuating equilibrium between glucose uptake, storage, and use in chickens. It is crucial in creating rapid growth in broilers, maintaining production in layers, and facilitating flexibility in varying feeding program. While chicken possess relative insulin resistance to mammals, PI3K-mediated signal transduction still plays a pivotal role in maintaining glucose homeostasis and optimal nutrient use in poultry physiology (Zhang et al., 2025).

Glucose metabolism regulated through PI3K holds specific significance in chickens in consideration of their relative insulin resistance with respect to mammals (Zhang et al., 2025). PI3K activation could enhance partitioning of nutrients and lessen the incidence of fatty liver in layers, as well as enhance food efficiency in broilers (Cui et al., 2022). Nevertheless, the absence of in-depth poultry-specific studies highlights a significant knowledge gap and an important opportunity for future translational research.

Tumour suppression and oncogenic potential

The PI3K family genes provide a double role in cancer biology, functioning both as an oncogenesis driver upon dysregulation and a tumour suppressor via inhibitory family members (Rascio et al., 2021). In both birds and mammals, the PI3K/AKT/mTOR pathway is one of the most commonly involved signaling networks in aberrant cell proliferation, survival, and metabolic reprogramming (Cirone, 2021). Activation of catalytic isoforms, including PIK3CA (p110α) and PIK3CB (p110β), beyond required levels can lead to hyperactive cell growth and proliferation and a predisposition to oncogenic conversion (Tufail et al., 2024). Point mutations or other variations within these isoforms have been implicated in aberrant activation of downstream targets such as AKT and mTOR that drive tumour cell survival, angiogenesis, and metabolic reprogramming (Glaviano et al., 2023). Correspondingly, immune-related isoforms PIK3CD (p110δ) and PIK3CG (p110γ), upon dysregulation, can cause aberrant lymphoid proliferation and immune-related malignancies (Gurska, 2022).

PIK3C2G (Class II) was suggested to play tumour-suppressive functions in mammalian systems in a way where PIK3C2G down regulation could enhance carcinogenic susceptibility (Paoli, 2025). Similarly, PIK3IP1, in a negative manner acting on PI3K catalytic activity, acts as a brake on PI3K/AKT activity via direct contact of PIK3IP1 with p110 isoforms. Eliminating or knocking out this molecule releases such a brake and potentially fosters oncogenic activity. Conversely, preservation of such a facet forestalls uncontrollable growth and offers a physiologic anti-tumour barrier (Jia et al., 2024). Once more, PIK3C3 (Vps34), though otherwise known mainly to function in autophagy regulation, indirectly participates in tumour suppression through the removal of damaged organelles and inhibition of oxidative DNA damage prone to proceeding in malignant transformation (Rebollo Gomez, 2020).

This coordination of oncogenic and tumour suppressor functions is therefore meticulously regulated through PI3K catalytic, inhibitory, and regulatory crosstalk sub-units (Hoxhaj and Manning, 2020). For chickens, these functions are not only significant at a primary biology level but also at a productive level since oncogenic dysregulation can affect growth attributes, immune strength, and breeding efficiency. Bird species are also very popular model species for investigating oncogenic viruses like avian leucosis virus (ALV) and Mark's disease virus (MDV), where PI3K signaling was implicated in viral oncogenesis. It then puts the PI3K gene family on a fork between suppressing tumour and promoting cancer, and hence stringent functional studies in chickens are in demand in order to gain a deeper insight into these two facets of PI3K in health and disease (Wang, 2020).

PI3K oncogenic events in birds are not only of basic cancer biology significance but also have direct implications for viral oncogenesis caused by avian leucosis virus and Mark's disease virus (Niebora et al., 2024). Mammalian models dominate oncogenic PI3K studies, but birds provide an untapped comparative system for studies of agricultural as well as biomedical sciences (Vashishat et al., 2024).

Variation in PI3K genes and functional implications

Genetic variation of PI3K family genes occupies a central role in functional diversification and phenotypic variation in hens. It includes SNPs, InDels, CNVs, and regulatory mutations in coding as well as non-coding regions. Such kinds of variations exert effects on gene expressions, protein structure, and functional activity and thereby regulate key biological processes, including growth, immunity, reproductive power, and metabolism (Zwane, 2017).

Among the most common variants, coding sequence SNPs are in a position to generate amino acid substitutions and change enzymatic function or stability in the catalytic isoforms PIK3CA, PIK3CB, and PIK3CD (Masoodi et al., 2019). Non-synonymous SNPs in these genes can enhance or reduce lipid kinase activity and affect subsequent AKT/mTOR signaling in turn and alter traits like body weight gain, feed convertibility efficiency, or immune competence (McNeill, 2016). Functional mutations within PIK3CA were reported to be associated with enhanced growth performance and hypertrophy of the skeletal muscle, but mutations within PIK3CD can change lymphocyte proliferation and antibody production and directly influence resistance to diseases. However, deleterious SNPs can alter kinase domains and inactivate PI3K signaling and make birds susceptible to metabolic imbalance or decreased immune competence (Tian et al., 2022).

The identified SNPs in poultry influence various economically important traits. For example, gga-miR-3528 rs14098602 A > G is associated with increased early body weight, improved muscle mass, and better eviscerated weight, suggesting a potential role in modulating growth efficiency (Shi et al., 2025). Furthermore, there are reports on GWAS-identified SNPs located within the PIK3R4 regulatory region associated with egg weight and egg length, thus indicating that PI3K-associated signaling influences reproductive performances. Moreover, functional variants like PIK3R1 and PIK3R4 are significantly associated with higher body weight in different stages of growth, thus reflective of their contribution to metabolic and muscle developmental pathways (Ayuso et al., 2016).

Regulatory differences in promoters or untranslated regions (UTRs) within PI3K genes also have a profound impact by affecting transcription factor binding and gene expression (Barrett et al., 2012). Up regulation of growth-related genes such as PIK3CA and PIK3SB is usually correlated with increased anabolic signal and improved feed conversion, while overexpression of regulatory genes such as PIK3IP1 can suppress PI3K activity and decrease growth efficiency but safeguard against out-of-control proliferation and tumorigenesis. Likewise, polymorphisms within PIK3AP1 (BCAP) can affect immune signals by changing B-cell receptor and Toll-like receptor interactions and thus alter host immune responses to pathogens and vaccines (Nguyen, 2021).

Copy number variations (CNVs) add a further dimension to diversity by varying dosages of a few PI3K genes. More copies of growth-positive genes could potentially raise protein production and growth rates, whilst losses or reduced copies could disrupt metabolic and immune systems. Such structural variations could then act in conjunction with environmental stresses to account for production trait variance between lines and breeds (Bellmunt et al., 2015).

Functional consequences of PI3K gene variation thus have a multi-faceted nature. In broilers, favourable variants are usually selected to drive fast muscle accretion and optimal nutrient use, facilitating productivity directly (Ferguson, 2020). In commercial layers, favorable variants in PI3K-regulated ovarian signaling pathways can enhance follicle selection efficiency and egg production. In contrast, in native or dual-purpose breeds, survival-promoting variants in immune-related PI3K genes may primarily confer improved disease resistance and resilience to environmental stressors (Jorge et al., 2014). Notably, spontaneous genetic variations in inhibitory members such as PIK3IP1 serve as natural brakes, reflecting the evolutionary equilibrium between survival and production (Jackson, 2023).

PI3K variations are a genome reservoir of functional diversity and create growth, metabolic, immune, and reproductive traits in chicks. Unravelling these variations and ensuing molecular effects not only enriches basic biology but also presents opportunities for application in genomic selection, marker-assisted breeding, and precision management in broiler production (Albooshoke and Bakhtiarizadeh, 2019).

Recent observations suggest that PI3K gene variants, including SNPs, CNVs, and regulatory polymorphisms, are associated with variation in growth, immune response, reproduction, and metabolic traits in poultry (Albooshoke and Bakhtiarizadeh, 2019). However, most of the mechanistic links remain speculative given functional validation in avian systems is sparse. Only a few chicken-specific studies reported expression of PI3K isoforms to be associated with feed efficiency, immune response, and muscle accretion traits (Ayuti et al., 2025). In contrast, mammalian studies have demonstrated comprehensively how PI3K gene polymorphisms alter kinase activity, immune signaling, and growth control (Shaw and Cantley, 2006). Thus, inferences pertaining to the functional consequences of PI3K genetic variants in chickens are largely drawn from conserved principles of signaling demonstrated in mammals. Such comparative extrapolation provides a biological rationale but should be interpreted judiciously until poultry-specific functional and association studies—integrating GWAS, CRISPR-mediated editing, and multi-omics validation—are performed to establish causality (Albooshoke and Bakhtiarizadeh, 2019). These limitations should be considered when proposing PI3K genetic variants as targets for breeding or biomarkers in poultry.

Applications and implications in poultry production

Genetic improvement and breeding programs

PI3K signaling is involved in key biological processes in chickens, including muscle development, autophagy, metabolism, and immune cell activation (Albooshoke and Bakhtiarizadeh, 2019). Overall, a few studies show differential expression of PI3K genes in broiler vs. layer lines, between heat-stressed vs. control birds, and during follicle development, which implies that the activity of the PI3K pathway is associated with performance traits (Chaudhary and Mishra, 2024). Yet, to date, no published study in birds has conclusively linked specific polymorphisms or structural variants in PIK3 genes to growth rate, feed efficiency, immune responsiveness, or reproductive traits (Marchesi et al., 2021). Likewise, PI3K genes have not been included in marker-assisted or genomics selection programs commercially offered to poultry producers (Sodhi et al., 2013).

While conserved functions of PI3K signaling make the genes listed herein potential candidates for future genetic improvement, use of PI3K alleles as breeding markers is still purely theoretical until poultry-specific genome-wide association studies, functional assays, and validation of causal variants confirm their phenotype effects.

Nutritional regulation and precision feeding

Evidence from chicken suggests that insulin and IGF-1 stimulate PI3K/AKT signaling in hepatic and muscle tissues involved in protein synthesis and glucose metabolism (Yu et al., 2015). Some nutritional manipulations—amino acid availability or phytochemical-rich feed—exert effects on downstream targets of PI3K/AKT signaling in avian models (Sacheck et al., 2004). Most of these studies do not report altered expression of specific isoforms of genes encoding PI3K enzymes or even attribute growth effects to PI3K modulation. Thus, although nutrient-responsive stimulation of PI3K signaling is supported at the pathway level in chicken, its application as a nutritional regulatory target is merely preliminary (Dodd and Tee, 2012). Dietary influences on PI3K expression, kinase activity, or PI3K-dependent production endpoints should be interpreted with caution until mechanistic and dose-response studies are carried out in avian systems (Levine, 2004).

Disease resistance and immunomodulation

In chicken, PI3K signaling regulates leukocyte activation, cytokine receptor signaling, and autophagy-mediated defense mechanisms (Hua et al., 2019). Infection and vaccination experiments illustrate the stimulation of PI3K pathways in immune cells from chicken at the time of immune activation (Luo et al., 2022). No study has shown that genetic variation within PI3K isoforms confers pathogen resistance, enhances vaccine responsiveness, or provides an explanation for line- or breed-level variation in immunity. While mammalian data provide rationale that PI3K variants may influence immune phenotypes, direct avian genetic and mechanistic evidence is limited. Linking PI3K alleles to poultry disease resistance is therefore best regarded as a future research direction, which involves natural variant identification, immune trait association testing, and functional validation (Li et al., 2019).

Reproductive efficiency and egg production

Regulation of follicle growth in the ovary by PI3K genes, especially PIK3CA, PIK3CB, and PIK3C3, has direct implications concerning reproductive performance in layers and breeding flock (Hanlon, 2020). These genes control proliferation and steroid production by granulosa cells and follicle survival, ensuring frequent ovulation and ovum production. Follicles harboring mutations or regulatory changes that reduce PI3K pathway inhibition—such as downregulation of PIK3IP1—are more likely to escape atresia, thereby enhancing follicular survival and ultimately improving laying performance (Dong et al., 2022). Understanding these processes opens a way to adapt reproductive management to achieve selection lines with desirable PI3K alleles or direct their activity to diet and hormone manipulation. Increased PI3K signalization could extend reproductive lifetime and reduce flock replacement, improving breeding farms' economics (MacLeod et al., 2019).

Adaptation to stress and environmental resilience

Poultry are exceptionally vulnerable to environmental stresses like heat stress, oxidative stress, and feed deprivation, which adversely affect growth, immune function, and reproductive performance (Ahmad et al., 2022). The PI3K family genes confer molecular resilience to stress stimuli via stimulation of cell survival program, augmentation of anti-oxidative defense, and induction of autophagy (Kma and Baruah, 2022). Thus, PIK3C3 and PIK3R4 facilitate cellular recycling during nutrient deprivation, whereas PIK3CA and PIK3FB promote AKT signaling to suppress apoptosis during heat or oxidative stress (Kma and Baruah, 2022). Such activities not only boost survival but also maintain productivity in adversity. With an intensifying climate change scenario, identification and exploitation of PI3K-mediated stress response will be critical in producing climate-resilient poultry breeds and enhancing flock quality in high-input production systems.

Poultry health and oncogenic studies

Aside from production traits, PI3K genes remain a subject of research in poultry owing to model systems of oncogenesis and tumour suppression. Dysregulation of PI3K isoforms has been associated with viral cancers such as avian leucosis virus (ALV) and Mark's disease virus (MDV) and hence offers a relevant system to study PI3K-driven oncogenesis (Kumar, 2018). On the other hand, inhibitory proteins such as PIK3IP1 have natural tumour-suppressive activity to emphasize evolutionary trade-offs between growth and avoidance of disease. Such studies not only improve poultry welfare but also provide supportive comparative biomedical research wherein studies involving avian PI3K can be informative about human cancer biology and drug targets (Yang et al., 2022).

Future directions

Using CRISPR/Cas9 for targeted editing of PI3K genes

Genome editing tools, including CRISPR/Cas9, provide the opportunity to experimentally test PI3K gene functions in poultry (Mishu et al., 2024). Currently, there are very limited published avian studies that apply CRISPR directly to major genes including PI3K isoforms; moreover, there is no empirical data showing that editing PIK3CA, PIK3CB, PIK3CD, PIK3CG, or their regulators enhances growth, immune function, or reproduction in chickens (Kianpoor et al., 2025).

Therefore, CRISPR-based modification of PI3K isoforms is best regarded as a research tool for functional validation rather than as a breeding strategy. Priority targets shall include: Confirm whether naturally occurring PI3K variants alter protein activity, elucidation of genotype–phenotype relationships for growth, metabolism, or immune signaling while validating the contribution of PI3K regulatory modules PIK3R, PIK3AP1, and PIK3IP1-family genes to pathway modulation.

Multi-omics approaches (use of genomics, transcriptomics, proteomics, and metabolomics)

Multi-omics integration remains an essential future direction that will define PI3K regulatory networks in poultry (Lu et al., 2024). Transcriptomic, proteomic, and phosphoproteomic datasets reveal PI3K/AKT responses to nutritional, endocrine, and immunological stimuli in poultry; comprehensive multi-layer pathway mapping is still limited (Hu et al., 2023). Future research should focus on establishing tissue- and developmental-stage-specific expression patterns for isoforms and evaluate pathway activation during relevant stress condition of heat, feed restriction, and disease challenge. Furthermore, integration of genomic variants of PI3K genes with expression/function—eQTL/XQTL analysis to generate datasets to identify chicken-specific PI3K pathway characteristics without recourse to mammalian extrapolation.

Functional validation in poultry cell and animal models

While many proposed roles of PI3K isoforms in poultry physiology remain inferred from mammalian models (Albooshoke and Bakhtiarizadeh, 2019), in order to reduce speculation and strengthen causal inference: it is imperative to study PI3K perturbation by inhibitor, RNAi, or overexpression should be tested in primary avian cell culture systems. Moreover, Animal models designed to incorporate activation/inhibition of these pathways should investigate association with phenotypes of feed efficiency, immunity, reproduction, or stress tolerance. There are no reports in the literature at this time demonstrating that PI3K gene variants independently drive economically relevant trait differences in poultry. Functional testing should precede translational conclusions (Albooshoke and Bakhtiarizadeh, 2019).

Breeding programs based on PI3K-based selection indices

Whereas PI3K variants have been suggested as candidates for genomics selection, no GWAS, QTL, or marker validation studies in chickens have thus far identified PI3K alleles determining growth, feed conversion ratio, immune resistance, reproductive longevity, or stress tolerance (Lin and Chen, 2024). Thus, the inclusion of PI3K genes in the selection indices must be regarded as a long-term research goal depending on: Discovery of naturally segregating variants of PI3K at population scale and their potential association with production traits along with validation of functional mechanisms linking genotype to phenotype. After achieving this, it would be possible for PI3K markers to complement established breeding tools.

Future perspective

Future studies of PI3K gene family in poultry should proceed from descriptive inference to systematic experimental validation (Gholizadeh et al., 2012). Productive avenues of investigation include: variant discovery and population-level association studies, pathway-specific functional testing in avian systems, integrative multi-omics characterization of PI3K responses, and development of tractable cell and animal models to study PI3K perturbation. While PI3K genes may eventually contribute to breeding, nutrition, and flock health programs, provided reliable genotype-phenotype relationships are identified through future work, such applications remain speculative in poultry until empirically validated (Neethirajan, 2023).

Conclusions

The chicken phosphoinositide 3-kinase gene family is emerging as a key molecular focal point where hormonal, nutritional, immune, and environmental cues may converge to affect downstream physiological processes with relevance to poultry productivity. The 16 isoforms, catalytic, regulatory, adaptor, and inhibitory sub units, have been well implicated in mammals in diverse physiological processes such as skeletal muscle growth, nutrient sensing, insulin/glucose metabolism, immune cell activation, angiogenesis, autophagy, and reproductive regulation. Parallel findings in chicken and other avian species are now increasingly reported but remain very limited in scope and, for the most part, do not clearly establish direct causal links to production traits. Therefore, the PI3K/AKT/mTOR pathway should be considered as an attractive candidate regulatory system as it is not yet a validated determinant for economically relevant poultry traits, which include feed efficiency, carcass yield and quality, reproductive efficiency, immune resistance, and environmental stress tolerance. Genomic variation, including SNPs, CNVs, and regulatory polymorphisms in genes coding for different components of the PI3K pathway, might indeed constitute one of the causes for phenotype variability in birds; however, the size and direction of such effects will need a systematic assessment in functional genomic studies undertaken in birds. Because most mechanistic knowledge is derived from mammalian systems, significant gaps exist in our understanding of avian-specific PI3K biology, including insulin sensitivity patterns, regulation of follicular hierarchy, stress-adaptive metabolic programming, and differential immune responses. Given such gaps, future research will be critically dependent on an integrative approach that incorporates transcriptomics, proteomics, metabolomics, and epigenomics with models of targeted perturbation, such as CRISPR/Cas9 editing, RNA interference, and pathway-specific inhibitors to establish causality. The eventual experimental confirmation of PI3K-mediated regulatory mechanisms in avian models will provide valuable biological insights into potential precision breeding, nutrition, and health management strategies for enhancing performance and resilience in commercial poultry. This translates mammalian knowledge into poultry-specific applications, with further views toward the sustainable genetic and physiological improvement of future flocks.

Ethical statement

Not applicable.

Data availability statement

All data generated/used in this study are available within the manuscript.

CRediT authorship contribution statement

Yong Chen: Project administration, Methodology, Conceptualization. Muhammad Mujeeb Ullah: Writing – original draft, Visualization, Validation, Data curation, Conceptualization. Hanan Al-Khalaifah: Writing – review & editing, Writing – original draft, Visualization, Validation, Data curation, Conceptualization. Faiz-ul Hassan: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Data curation, Conceptualization.

Disclosures

The authors declare no conflicts of interest.