Ferroptosis is a regulated mechanism of cell death caused by the uncontrolled peroxidation of cellular lipids that has an unusual ability to propagate or spread between cells. Here we review studies identifying regulators of ferroptosis propagation to consider a working model that might explain this unusual feature. Recent findings implicating the spread of lipid peroxides and iron suggest that these main catalysts of ferroptosis may also be primary vehicles that can spread death between cells. Experiments revealing localized versus long-range effects of propagation are discussed, as well as sensitizing factors that may expand the propagative potential of death induced by Class II ferroptosis-inducing compounds. As ferroptosis propagation may underlie the loss of large groups of cells in degenerative diseases and may also have a specialized role in normal development, consideration of how ferroptosis can spread through propagative signals may be important for understanding both normal tissue dynamics and disease.

Neurons rely on precise nutrient-sensing mechanisms to sustain proteostasis and stress resilience across a lifetime. Among these, mechanistic target of rapamycin complex 1 (mTORC1) functions as a central metabolic hub, integrating amino acid availability, growth factor signals, and energetic status to coordinate protein synthesis, autophagy, and neuronal survival. Neuronal mTORC1 regulation is highly specialised, reflecting unique metabolic demands, axonal compartmentalisation, and dependence on long-term homeostatic control that is not shared by non-neuronal cell types. Beyond canonical PI3K–Akt and AMP-activated protein kinase (AMPK) signaling, emerging evidence highlights metabolic intermediates, most notably leucine-derived acetyl-coenzyme A (AcCoA), as critical upstream regulators that couple nutrient flux to mTORC1 activity via EP300-mediated Raptor acetylation. Chronic dysregulation of these pathways drives persistent mTORC1 hyperactivation, progressive autophagy impairment, and accumulation of proteotoxic species, collectively contributing to neurodegeneration. In Alzheimer’s disease, aberrant mTORC1 activity is linked to tau hyperphosphorylation and amyloid-β accumulation; in Parkinson’s disease, to α-synuclein aggregation and mitophagy failure; in Huntington’s disease, to impaired clearance of mutant huntingtin; and in amyotrophic lateral sclerosis (ALS), to dysregulated proteostasis in motor neurons. This mini review synthesizes current understanding of neuronal mTORC1 regulation, with an emphasis on the AcCoA–acetylation axis as an emerging metabolic control mechanism, its disease-specific implications across major neurodegenerative conditions, and the therapeutic opportunities these insights reveal upstream of mTORC1.

Spatial omics is a broad term referring to technologies that allow for biomolecules to be observed within their native tissue context. These technologies have been used by biomedical researchers to gain a better understanding of cellular interactions, tumor microenvironment dynamics, and immune cell infiltration. While the basic outputs, such as spatial coordinates, segmentation masks, and transcript/protein matrices, are provided by the instrument software, the true biological insights come from several downstream, specialized analysis steps. Since spatial omics remains a relatively new field, no unified analysis pipeline has yet been established to encompass all platforms. Most workflows are adapted from single-cell RNA sequencing analysis frameworks, while incorporating additional steps that are specific to spatial data, especially for imaging-based technologies. At the same time, the diversity of platforms, data modalities, and output formats has introduced substantial challenges for data representation, interoperability, and cross-platform integration, highlighting the need for flexible, spatially aware, and user-friendly data structures made specifically for imaging-based data not merely adapted from other methods. This review summarizes the general analytical steps following spatial omics data acquisition, commonly used data infrastructures and tools, existing gaps, and future directions in the field.

Secreted proteins mediate intercellular and inter-organ communication and are essential for coordinating physiological processes across tissues. Advances in proteomics and proximity labeling have greatly expanded the catalog of circulating secreted factors; however, for many of these molecules, their cognate receptors and mechanisms of action remain unknown. This lack of receptor annotation represents a major bottleneck in understanding systemic signaling networks and translating secretome discoveries into biological insights. In this review, we summarize and evaluate the strengths and limitations of current strategies for deorphanizing secreted proteins, including 1) biochemical approaches such as affinity purification–mass spectrometry and crosslinking-based receptor capture, 2) genetic screening strategies in both in vivo and in vitro systems, including RNA interference and Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR)-based perturbation and activation platforms, and 3) computational frameworks based on AI-driven protein structure modeling. Finally, we outline future directions aimed at accelerating ligand–receptor identification, including multiplexed screening platforms, approaches to improve sensitivity for low-affinity interactions, synthetic biology tools that convert transient binding events into stable readouts, and integration with single-cell and spatial transcriptomic technologies. Together, these advances provide a roadmap for transforming classical ligand deorphanization into a scalable, context-aware framework for decoding inter-organ communication.

Lymphatic endothelial cells (LECs) and the lymphatic vasculature have evolved from being viewed as passive conduits for fluid drainage and metastatic dissemination to active, dynamic regulators of inflammation and tumor immunity. In solid tumors, both tumor-associated and lymph node (LN)–resident LECs engage in complex interactions with their environment to orchestrate immune processes, including antigen transport and presentation to T cells, leukocyte recruitment and trafficking via chemokine gradients, and local immune modulation through the expression of co-inhibitory ligands such as programmed death-ligand 1 (PD-L1). These multifaceted roles enable LECs to either amplify effector responses or induce tolerance, profoundly influencing the efficacy of cancer immunotherapies depending on their activation state, tissue context, and molecular programming. This minireview synthesizes and discusses recent advances in tumor lymphangiogenesis, the role of LECs and their intensive crosstalk with the immune compartments, in the coordination of anti-tumor immune responses, with particular focus on LEC-autophagy as a lipid metabolic checkpoint controlling lymph node T cell egress, and its far-reaching implications for optimizing immunotherapy outcomes in solid tumors.

Caspase-2 is a key genome-surveillance protease that functions to kill or arrest cells with abnormal chromosome content, via PIDDosome-dependent and -independent mechanisms. However, this surveillance function presents a biological paradox in the liver, where physiological polyploidy, is essential for organogenesis, genomic buffering and adaptive stress responses to maintain liver homeostasis. While short-term caspase-2 loss promotes adaptive polyploidy, our recent work demonstrates that prolonged caspase-2 deficiency drives pathogenic hyperploidy, fuelling chronic inflammation, and increased age-associated hepatocellular carcinoma in mice. These findings underscore the need for tight ploidy control in the maintenance of liver homeostasis. They also highlight potential risks for therapeutic targeting of caspase-2 in fatty liver disease and suggest that pathways governing lipid metabolism also influence long-term tumour surveillance mechanisms. This perspective discusses caspase-2 as a guardian of hepatic genome integrity, and the dual, context-dependent roles of polyploidy in liver physiology and metabolic liver disease.

Background: Cystic fibrosis (CF) is a progressive genetic disease characterized by defective ion transport, mucus accumulation, chronic infection, and inflammation that drive airway damage and ultimately end-stage lung failure. Previous studies show that high levels of proteolytic enzymes in the sputum of CF patients correlate with declining lung function, but the related effects on distal lung extracellular matrix (ECM) and immune responses are unclear.

Methods: To address this gap, induced pluripotent stem cell (iPSC) lines from healthy donors and CF patients were differentiated into macrophages, and stimulated with lipopolysaccharide (LPS) to compare their inflammatory responses. Bulk RNA sequencing, functional assays, and secreted protein profiling revealed key differences between healthy and CF-derived macrophages, providing insight into how these cells may contribute to inflammatory responses in CF patients. Further, human lung ECM from distal CF lung tissue was isolated, used to generate ECM biomaterials, and combined with iPSC-derived macrophages from healthy and CF donors in vitro. Macrophage phenotype was evaluated through cytokine profiling and RNA sequencing.

Results: CF macrophage inflammation was dysregulated, with elevated baseline IL-8, IL-18, and MCP-1 expression, and a blunted inflammatory response to CF ECM compared to healthy macrophages. By using CF ECM and healthy macrophages, we characterized how healthy cells may be altered in a persistent CF milieu after anticipated CFTR modulator therapy.

Conclusion: These findings reveal altered innate immune behavior in CF and demonstrate the utility of iPSC-derived macrophages for modeling extrinsic immune-ECM interactions in disease.