Maternal nutrition is a critical determinant of foetal development and long-term health outcomes, shaping the trajectory of offspring well-being across generations. As an essential micronutrient, zinc is involved in diverse physiological processes that are essential for optimal growth, neurodevelopment, and metabolic homeostasis [1]. The significance of maternal zinc sufficiency during pregnancy is well-established, with research primarily focusing on immediate outcomes such as birth weight and neurocognitive development [[2], [3], [4]]. However, a comprehensive exploration of the enduring consequences of maternal zinc deficiency across successive generations remains a significant gap in our understanding of developmental and health trajectories.

Zinc is an essential trace element integral to the function of numerous enzymes, transcription factors, and signalling pathways involved in cellular growth and differentiation. Its role as a cofactor in DNA synthesis, cell division, and gene expression underpins its importance during periods of rapid foetal growth and organ development [5,6]. Moreover, zinc is recognized for its involvement in neurodevelopment, influencing processes such as synaptogenesis and neurotransmitter function [7,8]. Consequently, deviations from optimal zinc levels during pregnancy may disrupt these intricate processes, leading to a spectrum of adverse outcomes that extend beyond the immediate perinatal period.

The involvement of zinc in glucose metabolism is highlighted by its impact on insulin synthesis, secretion, and action. Zinc serves as an integral component of the insulin hexamer structure and is involved in the synthesis and processing of proinsulin [9]. Consequently, adequate zinc levels are crucial for maintaining insulin function and glucose homeostasis. Studies have demonstrated that zinc deficiency can impair insulin sensitivity and disrupt glucose regulation [10]. This disruption is often associated with decreased insulin receptor phosphorylation and compromised glucose transporter function. The interplay between zinc and insulin signalling pathways extends to the regulation of key enzymes involved in glucose metabolism, such as glycogen synthase and phosphoenolpyruvate carboxykinase (PEPCK). Zinc acts as an insulin-mimetic, promoting glycogen synthesis and inhibiting gluconeogenesis through its impact on these enzymes [11].

Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and the antioxidant defence system, is closely linked to zinc status [12]. Zinc serves as a cofactor for several antioxidant enzymes, including superoxide dismutase (SOD) and metallothioneins [13]. These enzymes play a pivotal role in neutralizing ROS and preventing cellular damage. In conditions of zinc deficiency, a reduction in the activity of these antioxidant enzymes can occur, leading to increased oxidative stress. This oxidative stress, in turn, contributes to insulin resistance, further exacerbating disturbances in glucose metabolism [12].

Inflammation is closely linked to both zinc deficiency and oxidative stress. Zinc deficiency can potentiate inflammation by activating proinflammatory transcription factors, such as nuclear factor-kappa B (NF-κB), and promoting the release of inflammatory cytokines [14,15]. Conversely, inflammation can induce zinc redistribution within the body, leading to decreased zinc availability in target tissues [16]. This bidirectional relationship contributes to a proinflammatory state that can impair insulin signalling and exacerbate insulin resistance.

Moreover, the anti-inflammatory properties of zinc are evident in its ability to inhibit the production of proinflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) [17]. Zinc achieves this by modulating NF-κB signalling and influencing immune cell function. The anti-inflammatory effects of zinc contribute to its potential role in mitigating insulin resistance and preserving glucose homeostasis.

Despite the wealth of knowledge on the acute effects of maternal zinc deficiency, our understanding of how these effects echo across generations is limited. This study aims to bridge this critical gap by examining the transgenerational impact of maternal zinc deficiency on the physiological parameters of Drosophila offspring. The Drosophila melanogaster model provides a valuable platform for investigating the multigenerational consequences of maternal nutrition due to its short generation time, ease of genetic manipulation, and conservation of essential biological pathways.

This study encompasses a holistic approach, delving into various facets of physiological well-being, including alterations in Drosophila body weight, locomotor performance, glucose metabolism, antioxidant defences, and inflammation. By assessing these diverse aspects, we aim to unravel the interconnected mechanisms through which maternal zinc status influences the health outcomes of successive generations.