Hypoxic-ischemic encephalopathy (HIE) represents one of the most devastating clinical challenges in neonatal medicine, arising when the neonatal brain suffers from oxygen deprivation combined with restricted blood flow. This injury leads to both acute mortality and chronic neurological impairments, including cerebral palsy, cognitive disabilities, and epilepsy. Therapeutic hypothermia—lowering the infant’s body temperature to approximately 33–34°C—remains the only evidence-based treatment that can reduce mortality and improve neurological outcomes. However, the limitations and accessibility issues associated with cooling therapy underscore the need for innovative and complementary treatments.

The concept behind using breast milk as a neuroprotective agent stems from its rich composition of biologically active components, including stem cells, cytokines, growth factors, and neurotrophic substances. These elements have shown potential to support neurogenesis, reduce inflammation, and promote repair in damaged neural tissues. Unlike oral administration, the intranasal route capitalizes on the unique anatomical connection between the nasal mucosa and the central nervous system, allowing breast milk constituents to bypass the blood-brain barrier and directly access the brain through the olfactory and trigeminal nerve pathways.

In the clinical protocol established at Semmelweis University, the treatment commenced within 48 hours after birth, coinciding with the critical therapeutic window for optimal neuroprotection in HIE. Fresh breast milk was meticulously collected from each infant’s mother and carefully administered into the nostrils under rigorous clinical supervision. The meticulous monitoring ensured the detection of any potential adverse respiratory or neurological reactions. Following the initial clinical phase, the therapy was transitioned to a home-based setting, wherein trained parents continued the intranasal administration for 28 consecutive days, supported by ongoing remote monitoring.

Remarkably, the study found no respiratory, circulatory, or neurological adverse events attributable to the intranasal breast milk treatment. This finding establishes a critical foundation for the safety profile of the procedure, affirming that breast milk, when delivered through the nasal passages, does not compromise neonatal physiological stability. This safety confirmation is a vital step before any large-scale efficacy trials can be pursued, providing reassurance to clinicians and families considering this innovative modality.

One of the notable obstacles encountered during the study was logistical rather than medical. The procurement and transport of breast milk from mothers residing in remote locations posed significant challenges. Dr. Ünőke Méder described instances where she personally traveled to distant, rural farms to collect milk, navigating difficult terrain where access was frequently impeded. These logistical complexities underscored not only the infrastructural demands of conducting such novel clinical research but also the psychosocial stress borne by families coping with traumatic early life events.

Supporting lactation among mothers who had undergone the emotional strain of a seriously ill newborn was another critical component of the study’s success. Initiating and maintaining breast milk expression under intense psychological pressure required specialized counseling and clinical support. This aspect highlighted the holistic nature of neonatal care, where maternal well-being and infant treatment strategies are deeply interconnected and must be addressed simultaneously to optimize outcomes.

From the parental perspective, engagement was more positive than initially anticipated. As Dr. Eszter Tarjányi noted, many parents found empowerment and solace in contributing directly to their infant’s care during a period fraught with uncertainty. Learning the precise technique for intranasal administration proved straightforward once the parents understood that the process was painless and safe for their child. This unexpected ease of parental involvement could play a crucial role in the future scalability and acceptability of the therapy.

The current research focuses exclusively on establishing the safety of intranasal breast milk administration in clinically and home-monitored environments. While the biological rationale and preclinical animal models are compelling, the effectiveness and long-term neurological benefits of this therapy remain to be rigorously evaluated in larger, controlled clinical trials. Existing studies from Germany and Canada on preterm infants with brain hemorrhages have previously hinted at potential neuroprotective effects of intranasal breast milk, lending preliminary clinical credence to this approach.

Should subsequent investigations confirm efficacy, intranasal breast milk therapy could revolutionize neonatal care, particularly in resource-limited settings where conventional cooling therapy is unavailable or impractical. The simplicity, cost-effectiveness, and biological compatibility of using a mother’s own fresh milk as a therapeutic agent would offer a sustainable, low-risk approach to addressing neonatal brain injury worldwide. Moreover, this method could extend neuroprotective care beyond hospital walls, integrating into home healthcare frameworks.

International interest in this therapeutic concept is already growing, with several countries exploring opportunities to adapt and implement the intranasal breast milk protocol. Such global collaborations would facilitate the collection of broader clinical data, drive standardized training programs for families and healthcare providers, and address cultural and infrastructural barriers. Through these efforts, intranasal breast milk therapy may emerge as a critical component of comprehensive neonatal neuroprotection strategies.

In summary, the research conducted at Semmelweis University pioneers a promising frontier in neonatal therapeutic interventions. By harnessing breast milk’s unique biological potential and combining it with innovative delivery methods, clinicians are charting a path toward safer, more accessible, and efficacious treatments for newborns afflicted by hypoxic-ischemic brain injuries. Establishing safety in real-world settings lays the groundwork for future studies that could ultimately transform global health outcomes for this vulnerable population.

Subject of Research: Neonatal hypoxic-ischemic brain injury and intranasal breast milk therapy
Article Title: Intranasal Breast Milk as a Novel Neuroprotective Treatment for Brain-Injured Newborns: A Safety Study
News Publication Date: Early 2025
Web References:

• Study published in Pediatric Research: https://www.nature.com/articles/s41390-026-04847-2
• DOI: 10.1038/s41390-026-04847-2
  Image Credits: Semmelweis University, Budapest, Hungary
  Keywords: Hypoxic-ischemic encephalopathy, neonatology, intranasal therapy, breast milk, neuroprotection, therapeutic hypothermia, brain injury, neonatal care, stem cells, neurotrophic factors, clinical safety, home-based therapy

Lactylation, a relatively recently identified post-translational modification, refers to the addition of lactyl groups to lysine residues on proteins. This modification is gaining attention due to its significant impact on chromatin regulation and gene expression, linking metabolic changes directly to epigenetic processes. Despite growing evidence implicating lactylation in various pathological states, its role in neonatal brain injury remains largely uncharted territory. The study by Wang and colleagues pioneers this investigation by systematically analyzing lactylation-related genes (LRGs) using state-of-the-art transcriptomic, proteomic, and metabolomic datasets derived from models of neonatal hypoxic-ischemic injury.

Multi-omics integration achieved in this research stands at the forefront of systems biology, enabling a holistic understanding of the molecular cascades activated post hypoxia-ischemia. The researchers employed robust bioinformatics tools to analyze gene expression profiles alongside metabolic alterations and lactylated protein quantifications, allowing for the identification of critical regulatory nodes within the HIBD molecular network. Their results highlighted a subset of LRGs exhibiting differential expression patterns tightly correlated with disease severity, suggesting these genes as potential biomarkers for early diagnosis or prognosis.

One of the most fascinating revelations of this study is the mechanistic insight into how lactylation modifies chromatin architecture in neuronal cells under hypoxic stress. By demonstrating increased lactylation on histones and other nuclear proteins, the team showed that lactylation facilitates the activation of pro-inflammatory and apoptotic pathways, exacerbating neuronal damage. These findings advance our understanding of the metabolic-epigenetic interface in HIBD, revealing an unappreciated layer of gene regulation that may be harnessed for therapeutic benefit.

Furthermore, the involvement of metabolic intermediates, especially lactate, is underscored as not merely a byproduct of anaerobic glycolysis but as a signaling molecule that profoundly influences histone lactylation. This functional role of lactate challenges prior conceptions and opens avenues to rethink metabolic contributions to brain injury outcomes. Wang et al. expertly dissect how aberrant lactate accumulation following ischemic insult potentiates pathological lactylation, disrupting cellular homeostasis and promoting neuroinflammation.

The deep profiling also unveiled potential cross-talk between lactylation and other post-translational modifications, such as acetylation and methylation, hinting at a sophisticated epigenetic regulatory network that determines neuronal fate after injury. The interplay among these modifications may orchestrate diverse gene expression programs that govern survival or death pathways in damaged neonatal brains. Elucidating this dynamic regulatory code holds promise for novel intervention points.

Significantly, the study’s comprehensive data reinforce the concept that lactylation-related pathways could serve as therapeutic targets. Pharmacologic modulation of lactylation levels—either by interfering with lactate metabolism or by directly targeting enzymes responsible for adding or removing lactyl groups—offers a tantalizing strategy for mitigating the devastating effects of HIBD. Such precision medicine approaches could shift treatment paradigms from symptomatic care to molecularly tailored neuroprotection.

Methodologically, the multi-omics approach employed by Wang and colleagues is exemplary for its depth and rigor. The researchers seamlessly integrated transcriptome sequencing with quantitative lactylomics and metabolomics, supported by meticulous validation experiments in cellular and animal HIBD models. Their pipeline exemplifies how modern technology can unravel complex biochemical landscapes and translate molecular findings into clinical relevance.

Equally compelling is the translational potential of these findings. Identifying lactylation-related biomarkers in accessible biofluids like cerebrospinal fluid or plasma may enable early, noninvasive detection of brain injury severity. This heralds a new era where clinicians can stratify risk, personalize treatment, and monitor therapeutic efficacy with unprecedented precision, ultimately improving outcomes for the most vulnerable patients.

While the study sets a new benchmark, it also raises compelling questions for future research: How can the temporal dynamics of lactylation during injury and recovery phases be mapped? What are the cell-type specific effects of lactylation in neurons versus glial cells? Could lactylation be exploited for enhancing regenerative responses in the neonatal brain? These open avenues are ripe for exploration.

On a broader scientific scale, this pioneering study shines a spotlight on lactylation as an emerging epigenetic modulator in brain pathology. By bridging metabolism and gene regulation, it invites the scientific community to rethink classical paradigms of neuroinjury and neuroprotection through the lens of metabolic-epigenetic cross-talk. The implications extend beyond neonatal brain damage to other neurological diseases with metabolic components.

In the era of precision medicine, uncovering metabolic-epigenetic interactions such as lactylation provides crucial insights that could revolutionize pediatric neurology. Wang et al.’s study is a vivid reminder of the power of integrative, multi-disciplinary research to transform our understanding of complex diseases and herald novel therapeutic frontiers.

The promise of lactylation-targeted therapeutics illustrates the exciting convergence of metabolism, epigenetics, and neuroscience. With such innovations on the horizon, hope is rekindled for affected newborns and their families confronting the daunting aftermath of hypoxic-ischemic insults. The challenge will be translating these molecular breakthroughs into safe, effective clinical interventions.

In conclusion, the comprehensive work by Wang and colleagues elucidates the enigmatic role of lactylation in neonatal hypoxic-ischemic brain damage. Their findings not only deepen mechanistic understanding but also chart a path toward novel diagnostic and therapeutic possibilities. As the science of lactylation rapidly evolves, it beckons a transformative era in combating neonatal brain injury with unprecedented molecular precision.

Subject of Research: Neonatal hypoxic-ischemic brain damage and the role of lactylation-related genes.

Article Title: Mechanisms of lactylation-related biomarker in neonatal hypoxic-ischemic brain damage analyzed through multi-omics data.

Article References:
Wang, X., Zhou, W., Chen, X. et al. Mechanisms of lactylation-related biomarker in neonatal hypoxic-ischemic brain damage analyzed through multi-omics data. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04538-4

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41390-025-04538-4