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The global context has shifted dramatically since publication of the first EAT–Lancet Commission in 2019, with increased geopolitical instability, soaring food prices, and the COVID-19 pandemic exacerbating existing vulnerabilities and creating new challenges. However, food systems remain squarely centred at the nexus of food security, human health, environmental sustainability, social justice, and the resilience of nations. Actions on food systems strongly impact the lives and wellbeing of all and are necessary to progress towards goals highlighted in the Sustainable Development Goals, the Paris Agreement, and the Kunming–Montreal Global Biodiversity Framework. Although current food systems have largely kept pace with population growth, ensuring sufficient caloric intake for many, they are the single most influential driver of planetary boundary transgression. More than half of the world's population struggles to access healthy diets, leading to devastating consequences for public health, social equity, and the environment. Although hunger has declined in some regions, recent increases linked to expanding conflicts and emergent climate change impacts have reversed this positive trend. Obesity rates continue to rise globally, and the pressure exerted by food systems on planetary boundaries shows no signs of abating. In this moment of increasing instability, food systems still offer an unprecedented opportunity to build the resilience of environmental, health, economic, and social systems, and are uniquely placed to enhance human wellbeing while also contributing to Earth-system stability. This updated analysis builds upon the 2019 EAT–Lancet Commission, expanding its scope and strengthening its evidence base. The first Commission defined food group ranges for a healthy diet and identified the food systems' share of planetary boundaries. In this Commission, we add an analysis of the social foundations for a just food system, and incorporate new data and perspectives on distributive, representational, and recognitional justice, providing a global overview on equity in food systems. Substantial improvements in modelling capacity and data analysis allow for the use of a multimodel ensemble to project potential outcomes of a transition to healthy and sustainable food systems. The planetary health diet (PHD) remains a cornerstone of our recommendations and can be seen as a framework within which diverse and culturally appropriate diets can exist. Robust updated evidence reinforces a strong association with improved health outcomes, large reductions in all-cause mortality, and a substantial decline in the incidence of major diet-related chronic diseases. The reference PHD emphasises a balanced dietary pattern that is predominantly plant-based, with moderate inclusion of animal-sourced foods and minimal consumption of added sugars, saturated fats, and salt. Successful implementation of the PHD requires careful consideration of cultural contexts and the promotion of culturally appropriate and sustainable dietary traditions. This diversity of contexts, bounded by the PHD's reference values, represents substantial flexibility and choice across cultures, geographies, and individual preferences. However, when confronted by climate, biodiversity, health, and justice crises, transformation will require urgent and meaningful changes in our individual and collective behaviours and our culture of unhealthy, unjust, and unsustainable food production and consumption. For the first time, we quantify the global food systems' share of all nine planetary boundaries. These food system boundaries confirm that food is the single largest cause of planetary boundary transgressions, driving the transgression of five of the six breached boundaries. In addition, food systems exert a notable impact on the transgressed climate boundary and on the ocean acidification boundary. Unsustainable land conversion, particularly deforestation, remains a major driver of biodiversity loss and climate change, highlighting the need for zero conversion of all remaining intact ecosystems. Food systems account for the near totality of nitrogen and phosphorus boundary transgression, emphasising the improvements needed in nutrient management, efficient nutrient redistribution, and circular nutrient systems. The massive use of novel entities in food production, processing, and packaging (ranging from plastics to pesticides) remains a major concern but is alarmingly understudied. Our assessment of justice integrates three dimensions—distributive, representational, and recognitional—within a human rights framing that includes the rights to food, a healthy environment, and decent work. Analyses reveal important inequities in access to healthy diets, decent work conditions, and healthy environments, disproportionately affecting marginalised groups in low-income regions. We therefore propose nine social foundations that enable these rights to be met, and are able to assess the global status of six. Enabling access to, affordability of, and demand for healthy diets is paramount. Equally crucial is the right to live and work within a non-toxic environment and a stable climate system, as we recognise the profound impact of environmental degradation on human health and wellbeing. Furthermore, a living wage and meaningful representation would allow individuals to actively participate in building healthy, sustainable, and just food systems. However, nearly half of the world's population falls below these social foundations, undermining their ability to meet basic human rights. At the same time, the dietary patterns of most (6·9 billion people) of the world exert pressures that threaten further planetary boundary transgression. The destabilising effect of unhealthy overconsumption on the Earth's systems highlights the importance of viewing healthy diets not just as a human right, but also as a shared responsibility.

The global context has shifted dramatically since publication of the first EAT–Lancet Commission in 2019, with increased geopolitical instability, soaring food prices, and the COVID-19 pandemic exacerbating existing vulnerabilities and creating new challenges. However, food systems remain squarely centred at the nexus of food security, human health, environmental sustainability, social justice, and the resilience of nations. Actions on food systems strongly impact the lives and wellbeing of all and are necessary to progress towards goals highlighted in the Sustainable Development Goals, the Paris Agreement, and the Kunming–Montreal Global Biodiversity Framework. Although current food systems have largely kept pace with population growth, ensuring sufficient caloric intake for many, they are the single most influential driver of planetary boundary transgression. More than half of the world’s population struggles to access healthy diets, leading to devastating consequences for public health, social equity, and the environment. Although hunger has declined in some regions, recent increases linked to expanding conflicts and emergent climate change impacts have reversed this positive trend. Obesity rates continue to rise globally, and the pressure exerted by food systems on planetary boundaries shows no signs of abating. In this moment of increasing instability, food systems still offer an unprecedented opportunity to build the resilience of environmental, health, economic, and social systems, and are uniquely placed to enhance human wellbeing while also contributing to Earth-system stability. This updated analysis builds upon the 2019 EAT–Lancet Commission, expanding its scope and strengthening its evidence base. The first Commission defined food group ranges for a healthy diet and identified the food systems’ share of planetary boundaries. In this Commission, we add an analysis of the social foundations for a just food system, and incorporate new data and perspectives on distributive, representational, and recognitional justice, providing a global overview on equity in food systems. Substantial improvements in modelling capacity and data analysis allow for the use of a multimodel ensemble to project potential outcomes of a transition to healthy and sustainable food systems.

The detection of cytosolic dsDNA by the cyclic GMP-AMP synthase (cGAS) is tightly regulated to avoid pathological inflammatory responses. Here, we show that the methyl-CpG-binding protein 2 (MeCP2), a major transcriptional regulator, controls dsDNA-associated inflammatory responses. The presence of cytosolic dsDNA promotes MeCP2 export from the nucleus to the cytosol where it interacts with dsDNA, dampening detection by cGAS. MeCP2 export partially phenocopies MeCP2 deficiency, leading to innate immune activation and enforcing an antiviral state. Finally, MeCP2 displacement from the nucleus following dsDNA stimulation disrupts its canonical function, leading to the reactivation of otherwise repressed genes, such as endogenous retroelements. Re-expression of the latter leads to the accumulation of DNA species feeding cGAS-dependent signalling. We thus establish a direct role of MeCP2 in the regulation of the breadth and nature of dsDNA-associated inflammatory responses and suggest targeting dsDNA-associated pathways or endogenous retroelements as therapeutic options for patients with MeCP2 deficiency. Mecp2 deficiency underlies Rett syndrome, a genetic disorder presenting with chronic low-grade inflammation of unknown origin. Here, the authors show that Mecp2 is a central regulator of the onset, breadth and nature of nucleic acid immunity.

Inflammatory signal termination is critical for the maintenance of homeostasis. Cyclic dinucleotides (CDN) are second messengers that trigger inflammatory responses through the activation of the Stimulator of Interferon Genes (STING) signaling platform. No broad-acting direct regulator of intracellular CDNs has been identified in mammals to date. We show that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a major DNA damage response actor, directly interacts with the intracellular 2′3′-cGAMP CDN through its kinase domain, tempering STING activation. DNA-PKcs also acts on the 3′3′-cGAMP bacterial CDN and pharmacological STING agonists, impacting their bioactivity and ability to mount optimal antiviral responses. STING agonism has been considered as a therapeutic avenue to alleviate immunosuppression in human pathologies. By uncovering DNA-PKcs as a CDN signaling modulator and CDNs as inhibitors of DNA-PKcs kinase activity, we provide critical insights into CDN regulation, with implications for the development of STING-targeting therapeutics.Competing Interest StatementThe authors have declared no competing interest.Footnotes* You are viewing Version 2, the most recent version of this article.

The detection of cytosolic dsDNA is tightly regulated to avoid pathological inflammatory responses. A major pathway involved in their detection relies on the cyclic GMP-AMP synthase (cGAS) that triggers activation of the Stimulator of interferon genes (STING) which subsequently drives the expression of inflammatory genes and type I Interferons (IFNs). Here, we show that the methyl-CpG-binding protein 2 (MECP2), a major transcriptional regulator, controls dsDNA-associated inflammatory responses. We show that the presence of cytosolic dsDNA promotes MECP2 export from the nucleus to the cytosol where it interacts with dsDNA, dampening cGAS activation. Our data also indicate that MECP2 export from the nucleus partially phenocopies MECP2 deficiency, leading to the expression of inflammatory and interferon stimulated genes, enforcing an antiviral state. Finally, we also show that MECP2 displacement from the nucleus following dsDNA stimulation is sufficient to disrupt its canonical function, leading to the reactivation of otherwise repressed genes, such endogenous retroelements of the Long interspersed nuclear element-1 (LINE-1) family. Re-expression of the latter led to the accumulation of DNA species feeding cGAS-dependent signaling and can be dampened by reverse transcriptase inhibitors. We thus establish a previously unforeseen direct role of MECP2 in the regulation of the breadth and nature of dsDNA-associated inflammatory responses. Furthermore, our results suggest that targeting dsDNA-associated pathways or pharmacological inhibition of LINE-1 may bear therapeutic hopes for Rett syndrome (RTT) patients that present with MECP2 deficiency.Competing Interest StatementThe authors have declared no competing interest.