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Lipidomics, a rapidly evolving discipline at the interface of biology and analytical chemistry, seeks to comprehensively characterize the lipid composition of biological systems. Driven by advances in mass spectrometry, chromatography and computational analysis, lipidomics has enabled the high-resolution mapping of lipid networks and their functional dynamics across molecular, cellular and organismal scales. In biomedical research, lipidomics is emerging as a powerful platform for biomarker discovery, enabling early diagnosis, prognosis, and therapeutic monitoring of cancer, metabolic, and neurodegenerative diseases. The field is also reshaping drug discovery by uncovering lipid-mediated pathways, identifying novel therapeutic targets, and refining assessments of drug efficacy and safety. Beyond medicine, lipidomic analyses are redefining food and nutrition science by elucidating how dietary lipids influence metabolic health and disease risk. In parallel, environmental and ecological lipidomics are emerging as powerful frameworks for assessing ecosystem health, tracking the impact of pollutants and exploring the biological consequences of climate change. Such approaches are also informing the discovery of sustainable lipid resources and the development of novel biotechnological and agricultural innovations. With its rapidly expanding analytical repertoire and cross-disciplinary relevance, lipidomics is poised to make substantial contributions to both fundamental biology and applied science. This Perspective aims to synthesise the current state of the field, delineate major analytical and conceptual challenges, and outline future directions for translating lipidomic knowledge into tangible societal and environmental benefits.

Childhood obesity is rising globally. Yet, few studies have examined the microbiome and proteome in early childhood in relation to this outcome, and most are cross-sectional by design. Early-life factors in the ABIS birth cohort (n = 16,683) were associated with obesity up to age 26 (mean follow-up 25.3 years, range 23.7-26.5 years): psychosocial stressors, smoking, infections, and diet in the first year. We assessed biomarkers, including cord blood metabolome (n = 290) and proteome (n = 358), by liquid chromatography, mass spectrometry, and Olink. Gut microbial composition at age one (n = 1,743) was assessed using stool samples and 16S rRNA sequencing. In this prospective longitudinal cohort study, significant differences were found in infants with future obesity, including elevated angiopoietin-like 4 (ANGPTL4), follistatin, and hepatocyte growth factor (independently of maternal weight) and reduced isocaproic acid, tryptophan, and oleic acid, with prenatal mediation. Akkermansia, asaccharolytic bacteria (Phascolarctobacterium and Senegalimassiliensia), and equol-producers (Adlercreutzia and Slackia) were depleted. Machine learning models selecting 40 most predictive features showed long-term prediction from birth proteomics and bacterial taxa at age one (area under the curve [AUC] = 0.83 ± .05, n = 1,877) and additional metrics, for example, parental and child body mass index in the first 8 years (AUC = 0.89 ± .02, n = 1,877), suggesting durable biological encoding. Proteomic markers across folds included fibroblast growth factor 19, ANGPTL4, sulfotransferase family 2A member 1, and interleukin 20. These findings suggest clinically relevant biomarkers indicating early-life regulation of bile acid metabolism, lipid storage vs. oxidation, and immune-metabolic signaling and pathways to prospectively prevent childhood- and adult-onset obesity across a 26-year predictive gap. IMPORTANCE: Understanding the origins of obesity is critical for developing preventive strategies, and early life represents a particularly sensitive window. This study leverages a large, general-population cohort with prospectively collected data, including parental body mass index (BMI), cord blood proteomics, and the gut microbiome at age one, linked to obesity outcomes over 26 years. Using integrated machine learning models, we show that in addition to parental BMI, specific proteomic and microbial markers present in infancy can predict long-term obesity risk, highlighting the role of early metabolic programming. Several key markers point to bile acid signaling as a mechanism connecting early microbiome development with fat accumulation and insulin regulation. By identifying these early-life predictors long before obesity manifests, these results provide new insights into intergenerational risk and suggest measurable targets for preventing obesity and related metabolic disorders from the earliest stages of life.

Given the prevalence of metabolic perturbations in a variety of neurological and neurodegenerative diseases, understanding and monitoring brain metabolism is a key step in our advancement of therapies. The details of the citric acid cycle were established at the beginning of the last century but only recently have its metabolic intermediates been observed in vivo in the brain. In this study, we employed orthogonal analyses to investigate metabolic alterations in response to acute neuroinflammation in vivo, demonstrating a multi-technique approach that could be used for future studies.Hyperpolarized [1-13C] pyruvate spectroscopy revealed an early decline in pyruvate metabolism via pyruvate dehydrogenase (PDH), leading to reduced 13C-bicarbonate formation. This metabolic disruption occurred despite the absence of structural or perfusion changes on conventional MRI. Further analysis of polar metabolites in the ipsilateral hemisphere confirmed ongoing inflammatory processes. These findings highlight the potential of this dual technique approach to inform upon metabolic changes due to neuroinflammation.Combining methods to probe metabolism in invasive (metabolomics) and non-invasive (hyperpolarized MRI) manners, this represents a promising translational approach for real-time metabolic assessments in an area of the body, the brain, where studying processes such as metabolism has traditionally been challenging. This study has demonstrated the approach to monitor changes in metabolism in response to inflammation in the brain.

Perfluorohexyloctane (F6H8) is a semifluorinated alkane recently approved for ophthalmic treatment of dry eye disease. Although considered locally safe for topical use, its structural similarity to persistent per- and polyfluoroalkyl substances (PFAS) raises concerns about systemic accumulation and long-term toxicity. To investigate potential hepatic effects, we examined the metabolic impact of F6H8 exposure in human HepaRG hepatocytes across a broad concentration range representing short- and long-term exposure scenarios. Combined targeted and untargeted metabolic profiling by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS) was performed on intracellular extracts and extracellular media. F6H8 induced pronounced, concentration-dependent metabolic alterations, many of which exhibited non-monotonic responses. Low concentrations primarily affected amino acid, fatty acid, and lipid metabolism, while central carbon metabolism was disrupted only at the highest exposures. Notably, a putative biotransformation product, perfluorohexyloctanoic acid, was detected, suggesting metabolic persistence and conversion to a PFAS-like structure. This metabolite showed strong associations with cellular metabolic profiles and elicited metabolic changes that only partially overlapped with those induced by the parent compound, indicating distinct biological activity following biotransformation. These findings indicate that F6H8 elicits broad metabolic reprogramming and may not be metabolically inert as previously assumed. Given its clinical use and structural similarity to persistent fluorochemicals, the results highlight the need for comprehensive, long-term safety assessment of F6H8 and related semifluorinated alkanes.

Emerging studies reveal that gut microbes can conjugate diverse amino acids to bile acids, known as microbially conjugated bile acids. However, their regulation and health effects remain unclear. Here, we analyzed early-life microbially conjugated bile acid patterns and their link to islet autoimmunity. We quantified 110 microbial bile acids in 303 stool samples collected longitudinally (3-36 months) from children who developed one or more islet autoantibodies and controls who remained autoantibody-negative. We identified distinct age-dependent trajectories of these bile acid amidates and correlated them with gut microbiome composition. We found that altered levels of ursodeoxycholic and deoxycholic acid conjugates were linked to islet autoimmunity as well as modulated monocyte activation in response to immunostimulatory lipopolysaccharide and Th17/Treg cell balance. These findings suggest that microbially conjugated bile acids influence immune development and type 1 diabetes risk.

Background: Minimally invasive biomarkers that can reliably distinguish adults with inflammatory bowel disease (IBD) from symptomatic controls are still lacking. We investigated whether serum lipidomics can provide a reproducible diagnostic signature for IBD and how such a signature performs in relation to relevant inflammatory markers.

Methods: Untargeted lipidomic profiling was conducted on serum from the Swedish SIC-IBD inception cohort, comprising adults referred for suspected IBD, symptomatic controls, as well as healthy controls. Candidate diagnostic lipids were identified using supervised machine-learning models in the discovery cohort and then evaluated in the independent, population-based Norwegian IBSEN III inception cohort of treatment-naïve adults. We examined the diagnostic performance of the lipidomic signature in combination with high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP).

Results: The discovery cohort included 96 IBD patients, 66 non-IBD symptomatic controls, and 48 healthy controls, whereas the validation cohort comprised 349 patients with IBD and 198 symptomatic controls (Table 1). In the discovery cohort, a serum signature of hs-CRP and the two top lipids, lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (O-44:5), demonstrated a high diagnostic performance (area under the curve [AUC] 0.80, 95% CI 0.73-0.87) compared with hs-CRP alone (AUC 0.70, 95% CI 0.63-0.79). When applied to the validation cohort, hs-CRP combined with the serum lipid signature significantly enhanced discrimination between IBD and symptomatic controls (AUC 0.79, 95% CI 0.75-0.83) compared with hs-CRP alone (AUC 0.68, 95% CI 0.64-0.73; P < 0.0001). As illustrated in Figure 1, among patients with available stool samples, combining FCP with hs-CRP and the lipid signature numerically improved diagnostic accuracy (AUC 0.89, 95% CI 0.86-0.92) compared with FCP alone (AUC 0.86, 95% CI 0.83–0.90).

Conclusion: We identified and externally validated a serum lipidomic signature that improves the diagnostic prediction of IBD when combined with hs-CRP. Although the blood-based model of hs-CRP, lactosyl ceramide (d18:1/16:0), and phosphatidylcholine (O-44:5) did not outperform FCP alone, it approached its diagnostic performance and further enhanced accuracy when integrated with FCP. These findings support added value these lipids and may offer insights into lipid-related pathways underlying IBD pathogenesis.

BACKGROUND: Lipidomics and its branch epilipidomics are rapidly advancing fields that explore the roles of native and modified lipids (e.g., oxidized, nitrated and halogenated lipid species), respectively, in biological systems. Dysregulation of lipid metabolism and signaling contributes to numerous diseases, including cardiovascular, metabolic, neurodegenerative, and inflammatory conditions. However, multiple challenges, including lack of standardization, limited data integration, and poor clinical translation, hinder progress. To address these, the COST Action EpiLipidNET (CA19105) established a pan-European network fostering collaboration across disciplines to accelerate lipid science and its application to health and disease.

AIM OF REVIEW: This review outlines the achievements of EpiLipidNET over its four-year duration, highlights key scientific contributions across five thematic working groups, and presents the future direction of its ongoing activities. The aim is to demonstrate how a collaborative, interdisciplinary framework can catalyze innovation in lipidomics and epilipidomics, enhance methodological harmonization, support early-career researchers, and bridge the gap between basic science, clinical translation, industry, stakeholders, and public engagement.

KEY SCIENTIFIC CONCEPTS OF REVIEW: EpiLipidNET structured its networking activities around (i) harmonization of analytical workflows, (ii) development of epilipidomics tools and data integration strategies, (iii) translational studies for clinical lipid biomarkers, (iv) investigation of lipid signaling mechanisms, and (v) dissemination and outreach. The network supported over 460 members globally, launched multiple training schools and scientific missions, produced 110+ publications, and fostered new initiatives in endothelial membrane lipidomics, food lipidomics, plant and algae lipids, and redox lipid biology. Its integrative approach sets a foundation for continued progress toward precision medicine and sustainable health interventions through lipid science.

Perfluorohexyloctane (F6H8) is a semifluorinated alkane increasingly used in medical applications. Emerging evidence, however, indicates that this compound can persist in biological systems and influence cellular processes. These observations suggest that the exceptional stability of F6H8, while beneficial for medical performance, may also have implications for long-term biological and health outcomes.

Per- and polyfluoroalkyl substances (PFAS) are highly persistent environmental pollutants that bioaccumulate in living organisms and are increasingly implicated in metabolic dysfunction-associated steatotic liver disease (MASLD). Mitochondria, as central regulators of energy and lipid metabolism, represent key subcellular targets of PFAS toxicity. While emerging studies have examined PFAS-induced mitochondrial dysfunction using whole-cell analyses, studies focusing on mitochondria-enriched cellular fractions and their functional alterations under steatotic conditions, despite their clinical significance, remain limited. Here, we analyzed mitochondria-enriched cellular fractions and the extracellular secretome from human HepaRG hepatocytes exposed to a PFAS mixture under both steatotic and non-steatotic conditions by using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). The PFAS mixture composition and concentrations reflected those commonly reported in human epidemiological data. We observed PFAS- and steatosis-driven effects on metabolism, including lipid buildup in mitochondria-rich fractions due to mitochondrial-lipid droplet contact, disturbances in cardiolipin levels, and increased extracellular abundance of acylcarnitines. Notably, PFAS-induced impact on mitochondrial metabolism was exacerbated in steatotic hepatocytes. Pathway analysis identified disturbances in lipid metabolism and inflammation-related pathways, including leukotriene metabolism, squalene and cholesterol biosynthesis, highlighting a shared metabolic signature across the PFAS-steatosis axis. Functional mitochondrial assays further showed that PFAS exposure suppressed respiratory capacity under both conditions, whereas steatosis alone increased basal mitochondrial activity but nearly abolished spare respiratory capacity. Together, these findings indicate that steatosis is associated with greater PFAS-related alterations in mitochondrial respiration and metabolic composition within the mitochondria-enriched fraction, supporting heightened susceptibility of steatotic hepatocytes to acute PFAS exposure.

Emerging evidence suggests that environmental contaminants can influence both human metabolism and gut microbiota composition. However, the specific effects of prenatal exposure to persistent organic pollutants (POPs) on host-microbiome metabolic interactions remain incompletely understood. In this study, we investigated associations between prenatal exposure to POPs, including organochlorine pesticides, polychlorinated biphenyls (PCBs), and per- and polyfluoroalkyl substances (PFAS), and growth, metabolic profiles, and gut microbiota composition in infants at three months of age. Prenatal POP exposure was strongly associated with alterations in the infant metabolome, particularly affecting lipid metabolism and microbiota-derived metabolites. Among the POPs examined, PCBs showed the most pronounced influence on both metabolic profiles and gut microbial composition. The most affected metabolic pathways included fatty acid metabolism, bile acid transformation, and steroid hormone biosynthesis. Furthermore, prenatal POP exposure significantly altered the composition of the gut microbiome. PCB exposure was linked to reduced Bifidobacterium bifidum and Lactobacillus paragasseri, and increased Erysipelatoclostridium ramosum, along with disruptions in bile acid and amino acid metabolism. These findings suggest that early-life exposure to POPs can disrupt host-microbiome metabolic interactions, potentially through perturbation of lipid- and amino acid-related pathways.