Cholesterol is an essential lipid component of membrane bilayers that maintains proper cellular function. Macrophages, key innate immune cells, are involved in organ development, tissue repair, defense against infection, and tumor progression. Accumulating evidence indicates that macrophages undergo significant reprogramming of cholesterol metabolism in response to external signals from diverse pathological microenvironments. This review provides a comprehensive overview of the cellular and systemic regulation of cholesterol metabolism homeostasis and examines how cholesterol metabolites regulate macrophage function. It highlights recent advances in targeting cholesterol metabolism for therapeutic purposes in various human diseases, including neurodegenerative diseases, atherosclerosis, bacterial and viral infections, and cancer.

Chhikara et al. reframe stromal interaction molecule (STIM) proteins as structural organizers of membrane contact sites, not just calcium-entry activators, in neurons. STIM2 maintains resting endoplasmic reticulum (ER)–plasma membrane (PM) junctions; STIM1 dynamically expands them during neuronal activity. This activity-dependent remodeling tunes ER–PM proximity and calcium coupling, shifting focus from channel gating to spatial organization.

Membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM) are essential for lipid transfer, calcium signaling, and membrane organization. While the formation and function of ER–PM contacts are increasingly well-characterized, the spatiotemporal regulation of their localization remains elusive. Emerging evidence using nanopatterned substrates, ultrastructural imaging, and protein localization analyses indicates that membrane curvature can act as a spatial cue for the recruitment of specific tethering proteins, influencing where contact sites form. This opinion article synthesizes recent advances linking membrane topography ER–PM contact organization and highlights systems where curvature actively orchestrates contact position through curvature-sensing proteins. It also outlines key unanswered questions about how membrane curvature integrates into broader signaling networks that govern organelle contact communication.

Red blood cell (RBC) production, or erythropoiesis, serves as a paradigm for studying cellular differentiation in both physiological and pathological contexts. While the transcriptional and epigenetic programs controlling erythropoiesis are well characterized, the metabolic regulation of this complex process remains underexplored. Recent discoveries that pyruvate kinase activators improve outcomes in sickle cell disease and thalassemia underscore the therapeutic potential of targeting metabolism in RBC disorders. However, further progress is limited by an incomplete understanding of the metabolic networks supporting erythropoiesis and RBC function. This review highlights emerging insights into erythroid metabolic reprogramming involving bioenergetic and biosynthetic processes, newly discovered pathways shaping the erythroid metabolome, and the promise and challenges of exploiting metabolic vulnerabilities in inherited and acquired red cell disorders.

The glycan makeup of membrane glycoproteins and glycosphingolipids at the cell surface is traditionally viewed as mature and static. Recent findings challenge this view, showing that selective glycan remodeling can redirect membrane glycoproteins back to the Golgi for another go. In this review we discuss the glycosylation processes in cells, with a focus on the terminal glycan chains on proteins and lipids that are capped by sialic acid sugars, and that engage the glycan-binding proteins of the galectin family. We highlight new studies demonstrating that growth factors trigger the removal of sialic acid by endogenous neuraminidases at the cell surface, leading to glycolipid–lectin driven endocytosis and retrograde traffic to the Golgi. This molecular circuit, termed the GlycoSwitch, introduces new perspectives on glycan-mediated regulation of cellular functions.

The Hippo signaling pathway has a critical role in regulating tissue growth, development, and tumor suppression. Mutations in NF2, which encodes the tumor suppressor Merlin, disrupt Hippo signaling, causing aberrant activation of YAP/TAZ and contributing to diseases, such as cancer and developmental disorders. Recent studies have identified novel mechanisms by which biomolecular condensation and phosphoinositides regulate Merlin function in Hippo signaling. Furthermore, NF2 deficiency sensitizes cells to ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation. In this review, I highlight the emerging roles of Merlin–YAP signaling in physiology and disease, focusing on its regulation through biomolecular condensates, its contribution to development and ferroptosis, and its implications for therapeutic interventions.

Lysosomes degrade damaged or unwanted cell/tissue components and recycle their building blocks through small-molecule transporters of the lysosomal membrane. They also act as signaling hubs that sense and signal internal cues, such as amino acids, to coordinate cell responses. Recently, the activity of several lysosomal metabolite transporters has been elucidated, bringing new insights into lysosomal functions. Cell biological and structural studies of lysosomal transporters have also highlighted their roles in recruiting signaling complexes to lysosomes and delineated how their substrates gate such hybrid transporter/receptor, or ‘transceptor’, function. In this review, we summarize recent progress in our understanding of lysosomal transporters, with a focus on the export of lysosomal degradation intermediates, the existence of lysosomal amino acid shuttles that regulate the redox state and pH of the lysosomal lumen, and the role of lysosomal transceptors in nutrient and immune signaling.

The canonical role of the ribosome is to translate the genetic code into functional proteins. Recent discoveries, however, redefine the eukaryotic ribosome, as a regulatory hub, that senses cellular cues and transmits signals to downstream pathways. The P-stalk, an integral component of the ribosomal GTPase-associated center, once viewed as translational supporter, is now emerging as a key regulatory ribosomal module. It has recently been recognized as an activator of the integrated stress response, reshaping the Gcn1/Gcn20→Gcn2 axis into the new Gcn1/Gcn20/P-stalk→Gcn2 order. The P-stalk's structural plasticity allows also the ribosome to rewire gene expression in response to cellular demands, including cytokine response. In this review, an updated functional portrait of the P-stalk is presented, encompassing both ribosome-dependent and -independent activities.

Virus-associated cancers, which account for ~15–20% of the global cancer burden, arise from infections with human oncoviruses. These viruses drive malignant transformation through diverse mechanisms but share common oncogenic features, including reprogramming host membrane signaling and trafficking. Such processes are tightly regulated by phosphoinositides (PPIn), essential organizers of membrane dynamics and signal transduction implicated in cancer development and progression. Oncoviruses exploit host PPIn metabolism to facilitate their replication and persistence, often leading to its dysregulation. In turn, this disruption can activate oncogenic signaling pathways that promote malignant transformation. In this review, we summarize how oncoviruses manipulate PPIn metabolism to sustain their life cycle and drive long-term interactions with host cells, ultimately contributing to tumorigenesis.

Embryo growth, morphogenesis, and patterning are complex processes that coordinate between cellular dynamics, fate specification, and multiscale physical forces. Understanding how robustness in embryo development is achieved despite inherent heterogeneities in gene expression, cell properties, and tissue growth is a fundamental question. Although various feedback between gene expression, signaling, and cell and tissue mechanics have been uncovered to confer robustness on developmental systems, measuring variability and robustness from a quantitative perspective often remains challenging. Furthermore, cell fate plasticity, a key mechanism that can confer robustness, is lacking in many developing tissues. This review highlights how recent technological and conceptual advances in quantitative approaches to biology help to overcome these bottlenecks, with a particular focus on how mechanochemical feedback, or alternatively, selectively tuned control parameters, ensure developmental robustness.

The cell cycle is governed by tightly regulated checkpoints and proteogenomic oscillations that ensure genomic fidelity during cell proliferation. Dysregulation of the cell cycle can drive oncogenic transformation, and this positions it as a pivotal target in precision oncology. Recent advances reveal how proteomic and post-translational dynamics orchestrate cell-cycle phase transitions that are aberrantly disrupted in cancers. Therapeutic targeting of the CDK4/6 represents a cornerstone of cancer therapy, but resistance mechanisms limit its clinical efficacy. Emerging strategies such as targeted protein degradation, synthetic lethality, and combination immunotherapies further expand the therapeutic window. These innovations, coupled with biomarker-driven precision medicine, exploit cell-cycle vulnerabilities and transform them into an active tool to combat human cancers more effectively. This review highlights emerging mechanistic insights underlying tumorigenesis driven by an aberrant cell cycle and proposes potential therapeutics aimed at cell-cycle machinery-relevant targets.

Innate immune sensing through cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) surveils cytosolic DNA from invading pathogens or damaged organelles and initiates a spectrum of immune responses. It is well established that upon 2′3′-cyclic GMP-AMP (cGAMP) binding, STING exits the endoplasmic reticulum (ER), traverses the Golgi to trigger interferon programs, and finally reaches lysosomes for signal resolution through degradation, revealing a tightly choreographed itinerary for cytokine-driven immunity. However, emerging studies reveal additional layers of spatiotemporal complexity: ER-resident STING tunes in messenger RNA translation and Ca2+ efflux, Golgi-localized STING functions as a proton channel that initiates H+-dependent autophagy and transcription factor EB-directed programs for organelle homeostasis, and various mechanisms for metabolic remodeling and cell fate determination. This review synthesizes emerging organelle-specific mechanisms of cGAS–STING, delineates their roles in physiology and disease, and discusses how an organelle-centric perspective may inform selective, context-sensitive immunotherapies.

Genes burst. Instead of being monotonously transcribed by a steady stream of RNA polymerases, active genes undergo transient and random pulses of transcription that are referred to as gene bursting. This property is ubiquitous and evolutionarily conserved from bacteria to humans, and reflects the inherent stochastic nature of most biological processes. The frequency and duration of gene busting events varies greatly between genes and is now recognized to be controlled by an intricate interplay between transcription factors, chromatin features, and the transcription machinery. Recent findings also point to proximal regulation of bursting by epigenetic chromatin states, a novel role of non-histone modifications, and of distal control of bursting patterns by enhancers. Uncovering the regulatory mechanisms of gene bursting sheds light on how cells maintain a diverse range of gene-specific expression by modulating the different kinetic parameters of bursting.

Stem cell-based embryo models provide an alternative system to study an elusive period of development. Programmed mouse embryo models have recently been generated by activating two endogenous regulatory elements via epigenome editing. In this forum article, we discuss this achievement along with the potential of translating it to engineering models of human embryogenesis.

RNA localization and local translation are widespread phenomena that play key roles in a plethora of cellular processes ranging from embryo patterning to general cellular functions. The traditional paradigm assigns localization elements to cis-acting RNA sequences which assemble into complexes that regulate mRNA transport and translation, and the mRNA is generally transported while remaining translationally silent. However, recent evidence has shown that the nascent protein can also play an essential role in RNA localization and can enable polysomes to control their own transport and be delivered where and when they are needed. Two such examples are reviewed: translation factories and centrosomal mRNAs. Their comparison highlights the key role of cotranslational interactions in the spatiotemporal control of protein synthesis and protein fate.

Aging is characterized by progressive structural and functional decline, driven partially by epigenetic alterations. While changes in DNA methylation, histone modifications, and chromatin accessibility are well studied, the role of three-dimensional chromatin organization in aging remains underexplored. Advances in chromosome conformation capture technologies have revealed hierarchical chromatin structures, including compartments, topologically associating domains (TADs), and chromatin loops, which are crucial for gene regulation. Emerging evidence suggests that aging changes these structures, leading to altered gene expression and cellular dysfunction. This review summarizes recent findings on age-associated chromatin reorganization, highlighting its impact on transcription and nuclear architecture. It also compares the roles of 3D chromatin organization in aging and senescence, highlighting shared and distinct features in these biological contexts.

Various mechanisms act in a coordinated manner to maintain proteostasis in different cellular organelles. Nevertheless, with aging, certain proteins escape proteostasis surveillance, misfold, and aggregate. This process can lead to neurodegeneration. Despite the cellular nature of proteostasis, it is regulated by intertissue communication. How these intertissue signaling mechanisms coordinate proteostasis across the organism is largely obscure. Recent studies unveiled that the transforming growth factor (TGF)-β signaling cascade is an organismal proteostasis regulator. Here, we focus on the known roles of the TGF-β pathway as a coordinator of proteostasis and describe the messengers and biological activities that are controlled by this pathway. We also discuss open questions and highlight the potential clinical relevance of these discoveries.

The intricate interplay between Wnt signaling and nicotinamide adenine dinucleotide (NAD+) biosynthesis has emerged as a crucial axis that influences aging and tissue regeneration. Wnt signaling, a key regulator of cellular proliferation, differentiation, and tissue homeostasis, intersects with NAD+ metabolism, a cornerstone of cellular energy balance and genomic stability. This relationship is mediated through shared regulatory pathways involving sirtuins, poly(ADP-ribose) polymerases (PARPs), and metabolic enzymes which are sensitive to cellular NAD+ levels. Dysregulation of either pathway is implicated in cancer, age-related decline, and impaired regenerative capacity. This review consolidates current knowledge of the Wnt–NAD+ axis and highlights its cooperative roles in maintaining tissue integrity and combating the effects of aging. Furthermore, it explores therapeutic approaches targeting this axis to restore tissue health and enhance the capacity for repair, thereby offering promising avenues for addressing age-associated pathologies.

Phosphoinositide (PIP)-mediated AKT signaling is essential for cellular homeostasis because it orchestrates crucial processes such as metabolism, survival, proliferation, and motility. Dysregulation of this pathway drives various pathologies, particularly cancer. Although cytosolic activation of AKT has been extensively studied, its emerging roles in the nucleus have gained attention over the past decade. The complexities of AKT compartmentalization and associated functional mechanisms remain largely unexplored. At the plasma membrane, AKT activation occurs at specialized microdomains and cell–cell junctions where it influences polarity, adhesion, and migration. In endosomes, PIPs coordinate intracellular trafficking and cytoskeletal organization with AKT signaling. Protein scaffolds refine AKT signal specificity by assembling complexes. In the nucleus, AKT interacts with the p53–PIP signalosome and specific kinases to regulate oncogenesis and chemoresistance. This review explores PIP-driven spatial regulation of AKT across cellular compartments, emphasizing its role in cellular responses and oncogenesis. Understanding AKT compartmentalization mechanisms provides valuable insights into cancer biology and novel therapeutic strategies.

Cells are constantly exposed to various stresses, including nutrient deprivation and genotoxic stress, which dynamically interact with cellular sensing pathways to influence metabolism, gene expression, and homeostasis. The integration of nutrient-sensing mechanisms and DNA damage response pathways is critical in cancer progression. While individual processes are well-characterized, their cross-regulatory mechanisms are just beginning to emerge. Deciphering the interplay between nutrient stress and DNA damage is crucial for elucidating the mechanisms underlying cellular responses to stress and developing therapeutic strategies for various diseases, including cancer. This review highlights the relationship between nutrient stress and DNA damage, especially its underlying sensing pathway and cell fate determination.

Defects in ribosomal machinery cause ribosomopathies such as Diamond Blackfan anemia, classically linked to impaired protein synthesis. However, emerging evidence places mitochondrial dysfunction as a critical downstream consequence of ribosomal insufficiency. Thus, is impaired energy metabolism, rather than translation alone, a key driver of ribosomopathies such as Diamond Blackfan anemia? This insight could reframe our understanding of disease mechanisms and could identify metabolic pathways as promising therapeutic targets.

Polo-like kinase 1 (PLK1) phosphorylates a plethora of different substrates to regulate key cell cycle processes that include, among others, mitotic entry, chromosome condensation, nuclear envelope breakdown, centrosome maturation, spindle assembly and chromosome biorientation, cytokinesis, and the deposition of the specialized centromere histone CENP-A. Addressing the exact spatial and temporal control of PLK1 activity in these processes and its dynamic interplay with protein phosphatases that counteract mitotic phosphorylation, most notably PP1 and PP2A, has proven especially puzzling. In this review, we focus on the main unknowns in the area of human PLK1 regulation, exploring more specifically an emerging concept that master docking sites, including newly discovered noncanonical motifs, trigger initial local activation of PLK1 that promotes subsequent localized spreading of phosphorylation.