Biology and Life Sciences

Abstract: Telomeres, the ends of linear chromosomes, form a cap composed of specific telomeric DNA asso-ciated with specialized proteins that ensures efficient protection against chromosome degrada-tion and, consequently, overall genome instability. Three main complexes have been implicated in chromosome end protection, namely telomerase, shelterin, and the CST complex (CTC1/Cdc13-STN1-TEN1). In a recent study, we uncovered mutants of the S. cerevisiae CST in which damage was sensed both by the two major spindle checkpoints and the major DNA damage checkpoint. In the best-studied of these mutants, stn1-sz2, the stability and organization of the mitotic tubulin spindle was profoundly affected, as were the organization of the centrosomes and the kineto-chores. Here, we find that the stn1-sz2 mutant is hypersensitive to deletion mutants of two mem-bers of the kinetochores, Ctf19 and Mcm21, which correlated with mis-localization of their asso-ciated subunit in the COMA complex, Okp1, during anaphase. Defects in interactions between the kinetochores and the tubulin spindle are entirely sensed by the SAC (spindle assembly check-point). Here, we find that some of the stn1-sz2 damage is recognized by the Mad2 checkpoint pro-tein independently from the SAC. The data presented here contribute to a better understanding of the damage in stn1-sz2, the prototype of novel mutants of telomeric CST characterized by mitotic-spindle-damage in addition to the classical telomeric-DNA-damage.

Abstract: Skeletal muscle aging arises from interacting defects in proteostasis, mitochondrial quality control, inflammatory signaling, neuromuscular integrity, regenerative capacity, and mechanical-metabolic plasticity, and may culminate in sarcopenia. Circular RNAs (circRNAs) are plausible regulators and biomarker candidates, but most evidence derives from developmental myogenesis, expression profiling, or non-aging atrophy models. This critical review organizes the literature around skeletal muscle aging and applies a four-level framework encompassing discovery, mechanistic support, in vivo causality, and functional intervention. We assess human linkage, species, treatment timing, locus of action, and endogenous or engineered modality separately. circSnd1 and circDdb1 currently provide the strongest combination of functional preclinical evidence and association with aged human skeletal muscle. circFUT10, circBBS9, circNEB, and circGLIS3 define less mature regenerative, discovery, histological, or muscle-quality domains. Non-aging atrophy studies, including circTmeff1 and engineered circmiR-29b, test whether proposed mechanisms remain active under defined catabolic stress. In the targeted literature reviewed here, no reported circulating circRNA has yet met the analytical, biological, and clinical requirements for a useful sarcopenia biomarker. Therapeutic development is constrained by quantitative target credibility, systemic skeletal-muscle exposure, post-onset functional efficacy in aged organisms, safety, reversibility, and independent replication. The field should now prioritize rigorous validation over additional descriptive cataloging.

Abstract: For decades, the prevailing interpretation, originating with Tobin (1944) and firmly supported by Benjamin and Tobin (1951), has been that “without a kidney, the renal fascia does not form.” However, this premise was based on specific anatomical specimens lacking both the kidney and the adrenal gland, and has never been systematically verified through modern diagnostic imaging. In this study, we utilized congenital unilateral renal agenesis as a natural subtraction experiment to re-evaluate the mechanical model of retroperitoneal fascial lamination. In all three adult cases identified from 5,509 non-contrast CT scans, a distinct fascial plane corresponding to the parietal lamina (outer layer) of the posterior renal fascia was invariably preserved, despite the lifelong absence of the kidney. A uniform thinning was observed on the agenesis side (mean 1.52 mm vs. 1.85 mm), suggesting the selective loss of the organ-dependent “inner lamina” and the autonomous formation of the system-derived “outer lamina.” Integrating fetal embryology, materials science, and mechanical modeling, this framework aligns with the early truncal stiffening (evolutionary front-loading) and the extracellular matrix (ECM) material phase transition occurring around 20 fetal weeks. These events induce a multiaxial tension field and orthogonal Poisson compression, which may drive the macroscopic lamination of the retroperitoneal fascia. We outline a conceptual “two-stage alignment model” consisting of passive Poisson compression followed by active mechanotransduction, suggesting that retroperitoneal fascial formation cannot be explained solely by organ dependency. Furthermore, we present a biomechanical “causal loop,” wherein the formed planar fascial sheets undergo a functional turn into active tensegrity cables that distribute and transmit the gravitational loads encountered during postnatal erect bipedalism.

Abstract: Extracellular vesicles (EVs) are membrane-enclosed structures released by virtually all cell types and are increasingly recognized as important mediators of intercellular communication in physiological and pathological conditions. Transient receptor potential (TRP) channels are widely expressed cation-permeable channels involved in the detection and integration of chemical, thermal, and mechanical stimuli, as well as in the regulation of intracellular Ca2+ signaling. Given the ubiquitous expression of both EVs and TRP channels, increasing evidence points to a functional interplay between them. In this review, we summarize the currently available literature on the interactions between TRP channels and EVs. We first discuss the role of TRP channels in EV release, focusing on the contribution of plasma membrane and intracellular TRP channels to Ca2+-dependent vesicle shedding and exocytosis. We then review evidence for the presence of TRP channels in EVs and their potential transfer to recipient cells, including their emerging use as biomarkers of disease. Finally, we discuss how EVs can modulate TRP channel activity and expression in recipient cells through their protein, lipid, and nucleic acid cargo. These interactions have been implicated in diverse processes, including neuronal communication, inflammation, cancer progression, chemoresistance, vascular dysfunction, and tissue injury. Overall, the available evidence supports a bidirectional relationship in which TRP channels regulate EV release and composition, while EVs can in turn modify TRP channel signaling in recipient cells. Further studies are required to determine the molecular mechanisms underlying this crosstalk and its physiological and pathological significance, which may provide new opportunities for disease biomarkers and therapeutic interventions.

Abstract: Glioblastoma (GBM) is a highly aggressive brain cancer with a poor outlook, highlighting the need for treatments that can target several tumor survival pathways. In this study, we tested the anti-proliferative effects of bitter melon (Momordica charantia) extract (BME) and examined how it changes gene expression in U87 MG glioblastoma cells. BME reduced U87 MG cell growth in both a dose- and time-dependent way, with an IC₅₀ of 659 µg/mL. RNA sequencing showed 908 genes were affected, with 380 upregulated and 528 downregulated. Analysis revealed that BME’s growth-inhibiting effects were linked to the activation of apoptosis, cellular senescence, ferroptosis, p53, and stress-response pathways, while key tumor-promoting pathways like PI3K-AKT, TNF, TGF-β, and cytokine-cytokine receptor signaling were suppressed. These results suggest that BME slows glioblastoma cell growth by boosting stress responses that inhibit growth and weakening survival signals. Overall, our findings offer a detailed look at how BME works at the transcriptome level and support further study of its active compounds as possible multi-target treatments for glioblastoma.

Abstract: Multiplicative threshold models are widely used to describe biological commitment steps. In their common form, a global permissive factor scales the product of locally acting terms, so a change in cellular state multiplies every substrate’s output by the same number. We show that this form has two problems. First, it is structurally unidentifiable: in a factorial design the permissive factor and the local terms are defined only up to a constant that can be traded between them, so the field has no absolute scale unless an external measurement anchors it or a substrate class responds with opposite sign. Second, where the required measurements exist, the form is empirically false. We reanalysed a published reporter series in Candida albicans in which 5′ leader architecture, amino-acid starvation, and global protein synthesis rate were measured in one experiment. A single scalar field mispredicts translational output by up to 8.6-fold, with a leave-one-out prediction error of 1.29 log units. A field indexed by leader class fits well (0.16 log units) and separates transcripts into three non-overlapping response classes. Without being fitted to it, the class comprising leaders with no inhibitory element recovers the independently measured global synthesis rate, placing that measurement at the 60.5th percentile of its bootstrap distribution. Repression strength does not substitute for architectural class: a structural element repressing 200-fold stays coupled to the global field, while an upstream open reading frame repressing 120-fold escapes it. Leader architecture therefore selects which field a transcript obeys rather than scaling a common one. We give the minimum design that identifies such a model.

Abstract: Type 2 diabetes (T2D) has long been viewed as a disease driven primarily by progressive loss of pancreatic β-cells resulting from chronic metabolic stress and apoptosis. Increasing evidence, however, indicates that impaired insulin secretion frequently arises from disruption of β-cell identity rather than extensive cellular depletion. Under diabetic conditions, mature β-cells may relinquish their differentiated phenotype through dedifferentiation, acquiring progenitor-like characteristics, or undergo transdifferentiation toward alternative endocrine cell fates, particularly α-cell-like phenotypes. These observations have shifted the current understanding of T2D toward a disorder characterized by β-cell plasticity and altered cell-state dynamics. In this review, we examine evidence from human pancreatic tissues, lineage-tracing studies, single-cell transcriptomic analyses, and experimental models to summarize the molecular mechanisms responsible for β-cell dedifferentiation and transdifferentiation. Particular emphasis is placed on the contribution of glucotoxicity, lipotoxicity, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory signaling, and epigenetic regulation in destabilizing β-cell identity. To complement the published literature, we performed an integrated systems-level bioinformatics analysis of ten established regulators of β-cell identity, including PDX1, MAFA, NKX6.1, FOXO1, ALDH1A3, NEUROG3, BACH2, TCF7L2, UHRF1, and SMOC1. Functional enrichment and interaction network analyses revealed extensive coordination among pathways involved in pancreatic development, endocrine differentiation, glucose homeostasis, chromatin regulation, and diabetes-associated signaling, highlighting the interconnected molecular framework that maintains β-cell fate. We further discuss emerging concepts of endocrine plasticity, including β-to-α-cell conversion, hybrid endocrine cell states, and the growing evidence that β-cell dedifferentiation may be reversible. Finally, we evaluate current and emerging therapeutic strategies aimed at restoring β-cell identity through metabolic interventions, incretin-based therapies, epigenetic modulation, and regenerative approaches, emphasizing the potential of preserving or re-establishing endogenous β-cell function rather than simply enhancing insulin secretion.

Abstract: Left ventricular pressure overload (LVPO) is a common hemodynamic stressor in pediatric cardiovascular diseases, yet how progressive—rather than fixed—overload reshapes the neonatal left ventricular (LV) developmental program remains largely unexplored. In this study, we established a neonatal rat model of progressive LVPO via abdominal aortic banding surgery (ABS) on postnatal day 1(P1), achieving 100% survival. Model validation was confirmed by abdominal ultrasound and serial blood pressure monitoring from P21 to P35, demonstrating sustained increases in flow velocity and arterial pressures. To investigate the transcriptomic impact of progressive overload, we performed RNA-sequencing on LV free walls at P3 and P7. The total number of differentially expressed genes (DEGs) between P7 and P3 was comparable between normal development (2,927 DEGs) and overload conditions (3,132 DEGs); however, principal component analysis revealed a marked shift in the LV developmental trajectory under overload, indicating qualitative reprogramming. Among 1,550 shared DEGs, enrichment for cardiac proliferation was observed, yet the cellular phenotypes diverged: normal development exhibited declining Ki67⁺ cardiomyocytes, whereas overload progressively increased proliferation. Importantly, 1,377 DEGs unique to normal development were enriched in oxidative phosphorylation and metabolic pathways, suggesting that overload blunts normal maturational cues. Conversely, 1,582 DEGs exclusively expressed under overload were enriched in angiogenesis and VEGF signaling, with validated upregulation of Adam8, Dll1, and Ptgs2. Collectively, our findings demonstrate that progressive LVPO does not simply damage the neonatal heart but actively reprograms LV development by sustaining cardiomyocyte proliferation via metabolic maturation arrest, extinguishing normal maturation, and inducing compensatory angiogenesis.

Abstract: Background: For appropriate glucose sensing, pancreatic beta-cells essentially establish a constant mitochondria-directed endoplasmic reticulum (ER) Ca²⁺ leak via phosphorylated presenilin-1. In the current work, we investigated how cells maintain the ER Ca²⁺ content during this continuous Ca²⁺ leak. Methods: Ca²⁺ imaging for ER, cytosolic and subplasmalemmal Ca²⁺, high resolution respirometry, and ELISA for insulin secretion were used. Results: A novel ER Ca²⁺ refilling mechanism driven by reverse-mode of NCX2, which is fueled by local Na⁺ influxes through TRPC3 and TRPV4 channels that are independent from STIM-ORAI1 was found in pancreatic beta cell lines. Disrupting this TRPs-NCX2 axis reduces subplasmalemmal Ca²⁺ levels, abolishes glucose-induced cytosolic Ca²⁺ oscillations, suppresses glucose-triggered elevation in mitochondrial energetics, and impairs first-phase insulin secretion. Conclusions: We identified a novel, ORAI1-independent "TRPs-NCX2" relay that couples Na⁺ influx via TRPC3 and TRPV4 to NCX2 reverse mode to maintain ER Ca²⁺ stores during physiological basal (ER) Ca²⁺ leakage, which is fundamental to beta-cell responsiveness to elevated glucose.

Abstract: CCDC69 was previously identified as a gene upregulated during adipogenic differentiation of human Simpson–Golabi–Behmel syndrome (SGBS) preadipocytes but not mouse 3T3-L1 preadipocytes. Here, we investigated the role of CCDC69 in adipogenesis using SGBS cells. CCDC69 expression during adipogenic differentiation was assessed by quantitative reverse transcription PCR and Western blotting. CCDC69 function was examined by adenovirus-mediated overexpression and knockdown, followed by analyses of lipid accumulation, adipocyte marker expression, cell morphology, and cytoskeletal organization. CCDC69 expression increased during adipogenesis. CCDC69 overexpression enhanced adipogenesis, as indicated by increased lipid accumulation, a higher proportion of cells containing lipid droplets, and increased expression of adipocyte marker genes and proteins. Unexpectedly, CCDC69 knockdown also enhanced adipogenesis. Time-course analysis showed that CCDC69 overexpression suppressed PPARG mRNA expression during early adipogenesis but increased its expression at later stages, whereas knockdown increased PPARG expression at later stages. CCDC69 overexpression induced a flattened cell morphology accompanied by reduced fibrillar α-tubulin structures and F-actin stress fibers and increased punctate F-actin structures, whereas knockdown increased the number of small, round cells. These findings indicate that CCDC69 may regulate adipogenesis in a stage-dependent manner and is associated with adipocyte morphology and cytoskeletal organization.

Abstract: This article introduces the concept of enosis – the ability of life forms to adapt by accessing each other’s molecules, structures, information and other contents – and discusses the roots and implications of this concept using cancer and cancer therapy as a case study.

Abstract: The genetic architecture of neurodevelopmental disorders (NDDs) is increasingly well described, yet the biological meaning of many variants remains uncertain. A molecular diagnosis may identify the affected gene without explaining how the alteration perturbs brain development or why the same or related variants produce different outcomes. Variant effects are conditioned by dosage, developmental timing, cell identity and the wider genomic, epigenetic and environmental context, while compensatory responses may modify or obscure the phenotype. Functional interpretation therefore depends on linking the molecular defect to the relevant developmental and physiological consequences. This review brings together current knowledge of NDD mechanisms with the experimental and computational strategies used to test that link. No model reproduces the complete disorder, and greater complexity does not necessarily confer greater validity. The most informative system is the one that captures the biological process and developmental window relevant to the question. Concordance across models can strengthen a proposed mechanism, whereas discordant findings may reveal cellular, developmental or species-specific effects that would otherwise be missed. The same standard applies to therapeutic development: correction of a molecular abnormality is meaningful only when it produces durable functional benefit and can be achieved with appropriate central nervous system distribution, dosage and safety. Integrating functional evidence with detailed phenotyping and longitudinal clinical data may improve variant interpretation, distinguish biologically meaningful patient groups and support therapeutic strategies directed at mechanism rather than diagnostic category.

Abstract: Extracellular lipid-containing particles are usually interpreted as extracellular vesicles, lipoproteins, soluble lipid mediators, or carriers of molecular cargo. This article proposes the lipid-state transduction hypothesis (LST), a falsifiable framework in which a cellular or tissue state can be materially represented in an extracellular lipid-state interface, partially retained during externalization, remodeled by biological fluids, and converted through biological sampling into a functional state input. LST reframes lipid state as a causal variable in extracellular particle biology, linking source-state writing, lipid composition and interfacial organization, particulate presentation, fluid-phase editing, routing, and target-cell sampling to biological function. LST is developed in weak, intermediate, and strong forms. Weak LST places lipid-state transduction within known extracellular vesicle and lipoprotein biology. Intermediate LST emphasizes that carrier form, interfacial presentation, and fluid-phase identity can transform how a source-associated lipid state is routed and interpreted. Strong LST predicts a lipid-state-dependent functional layer beyond established extracellular particle classes and cargo-centered mechanisms. The key empirical prediction of strong LST is the existence of non-classical lipid-state transduction particles (non-classical LSTPs). Operationally, these candidates are expected to appear as extracellular lipid-dominant particle-like or complex-like components with low abundance of canonical extracellular-vesicle markers and classical apolipoprotein markers. Functionally, they are candidate entities predicted to participate in lipid-state transduction and are defined by source-state association, lipid-state-dependent activity, and a positive causal residual when conventional particle-, cargo-, and artifact-based frameworks cannot sufficiently explain their effects. Thus, non-classical LSTPs are not proposed as a marker-defined particle class, but as lipid-state-dominant functional entities within a transduction process. At a broader level, LST shifts extracellular lipid biology from particle identity and cargo attribution to state causality. It opens a conceptual space in which membrane-derived lipid organization may act as a material state-bearing interface that is externalized, fluid-edited, routed, and biologically sampled, thereby linking source-cell or tissue state to homeostatic regulation, injury interpretation, and disease-relevant extracellular responses.

Abstract: DNA repeats and protective proteins, which comprise telomere complexes, are crucial for genomic integrity; however, the inherent limitations of DNA end-replication through cell divisions lead to age-dependent telomere shortening. Telomere attrition, besides being a quintessential characteristic of aging, acts as a natural tumor suppressor mechanism by inhibiting unlimited cell division. Constitutive telomere length, a heritable trait, is associated with various cancers. Oxidative DNA damage and replicative stress, driven by genetic, epigenetic, and environmental factors, also contribute to telomere shortening. Besides, telomere maintenance dynamics within tumors and within cells in the tumor microenvironment critically influence outcomes in different cancers. Within tumors, despite activated elongation mechanisms, various functional constraints result in short telomeres, indicating a crucial role for telomere biology components in cancer outcomes. In this review, we explored the telomere length in leucocytes and cancer tissues in relation to risk and survival in major gastrointestinal cancers, including colorectal, pancreatic, and esophageal cancers.

Abstract: Sweet potato (Ipomoea batatas L.) is an important food security crop in developing countries, but production is constrained by virus-infected planting material from vegetative propagation. This study evaluated selected combinations of plant growth regulators (PGRs) for in vitro propagation of orange-fleshed sweet potato cv. 'Kulfo'. Nodal and apical shoot explants were cultured on Murashige and Skoog (MS) medium with different combinations of 6-benzylaminopurine (BAP) and gibberellic acid (GA₃) for shoot initiation, BAP and naphthalene acetic acid (NAA) for multiplication, and indole-3-butyric acid (IBA) and NAA for rooting. Among the treatments tested, MS medium with 0.5 mg L⁻¹ BAP and 0.1 mg L⁻¹ GA₃ gave the highest shoot regeneration (62% from nodal and 59% from apical explants). For multiplication, 1.0 mg L⁻¹ BAP with 0.1 mg L⁻¹ NAA produced the highest shoot number (7.2 shoots per explant). Half-strength MS medium with 0.1 mg L⁻¹ IBA and 0.1 mg L⁻¹ NAA resulted in the best rooting response (13.3 roots per shoot). Plantlets from the best-performing treatment achieved 98.0% survival during acclimatization. However, the limited PGR concentrations tested mean that these results should be considered preliminary. Further optimization using broader concentration gradients is needed to establish a truly optimized protocol. This study provides a foundation for developing cultivar-specific micropropagation protocols for sweet potato in Ethiopia.

Abstract: Quantitative image analysis is an important basis for turning microscopy observations into reproducible data. Its throughput and reproducibility depend on the analysis software, and CellProfiler is useful because it builds an analysis pipeline by combining modules at a relatively low cost, without requiring programming. In the gonad of the nematode Caenorhabditis elegans, germ cells are arranged along the distal–proximal axis in an order that reflects their developmental stage. Yet this highly organized arrangement has rarely been quantified, though its disruption could reveal mutant phenotypes. In this study, we built a CellProfiler pipeline that measures the nuclear area and the centroid-to-centroid distance between germ-cell nuclei in the C. elegans gonad. We first examined the object-detection conditions and found that the minimum and maximum diameter settings, together with visual confirmation, are important for reliable recognition. Applying the pipeline to DAPI-stained germ-cell nuclei in the distal arm at the late L4 stage, adult day 1, and adult day 3, we found that the nuclear size was small at the L4 stage and did not differ between adult day 1 and day 3. This pipeline enables quantitative analysis of germline development within the animal and of abnormalities revealed by mutant analysis.

Abstract: Background: Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) are under investigation as cell-free therapeutic platforms for neurodegeneration and age-related disease, and their biological effects depend partly on cargo composition. Existing MSC-EV cargo studies rarely integrate disease-gene evidence, aging databases, publication-level support and translational annotation. Methods: Using public data only, we assembled documented human MSC-EV cargo from ExoCarta and Vesiclepedia, deduplicated to independent source publications, and retained proteins with support from at least two publications. Each protein was integrated across independent-publication support, neurodegeneration disease-gene evidence (Open Targets), aging/senescence membership (CellAge, GenAge) and protein-interaction centrality (STRING) into a four-component Cargo Prioritization Score (CPS), after a component-correlation analysis. Robustness was assessed by weighting, component and source-study analyses; enrichment used the MSC-EV cargo universe as background; and top candidates received a separate Computational Liability Annotation (LOEUF, oncology association, expression breadth) with structured directionality curation. Results: The reproducible universe comprised 815 proteins derived from 9 source publications; disease-breadth was removed for redundancy with the neurodegeneration score (Spearman ρ=0.93). The ranking was robust to weighting (equal-weight ρ≈0.99) and to removal of any single component (ρ=0.83–0.94), but the eligible universe and several disease-anchored candidates depended strongly on individual source publications: excluding one publication reduced the universe from 815 to 228 proteins. 43 proteins carried joint neurodegeneration and aging evidence, including VCP, PARK7, SQSTM1, SOD1 and APOE, whereas the highest ranks partly reflected abundant, broadly expressed or highly connected proteins (GAPDH, ACTB, ALDOA, EGFR). Conclusions: The framework integrates evidence to prioritize MSC-EV cargo and separately annotates translational directionality and liability. A high CPS does not establish beneficial delivery, and the annotation is not a safety assessment; the output is a translationally annotated, hypothesis-generating candidate set for product-specific experimental validation.

Abstract: Background: Bone regeneration requires coordinated regulation of osteogenesis angiogenesis, extracellular matrix remodeling, immune responses, and mineralization. Extracellular vesicle (EV)-based therapies have emerged as promising cell free strategies, although their molecular mechanisms remain incompletely understood. Objective: To investigate the molecular mechanisms potentially underlying the osteoregenerative effects of an EV concentrate using an in silico systems biology approach. Methods: Five osteogenesis and immunomodulation related microRNAs (hsa-miR-146a-5p, hsa-miR-21-5p, hsa-miR-335-5p, hsa-miR-503-5p, and hsa-miR-129-5p) were analyzed. High-confidence target genes were identified using TargetScan 8.0, followed by overlap analysis, Gene Ontology and KEGG enrichment, and miRNA-mRNA network reconstruction in Cytoscape. Results The selected miRNAS regulated hundreds of predicted targets, displaying complementary rather than universal target overlap. SMAD7 emerged as a key shared regulatory node involved in TGF-β/BMP signaling. Functional enrichment demonstrated significant associations with osteoblast differentiation, angiogenesis, extracellular matrix organization, inflammatory regulation, and mineralization. Pathway analysis identified convergence on MAPK, Wnt/β-catenin, TGF-β/BMP, PI3K/Akt, FoxO, Hippo, AMPK, and NF-κB signaling. Conclusions: These findings indicate that EV concentrates may promote bone regeneration through coordinated miRNA-mediated regulation of multiple osteoregenerative pathways, providing a mechanistic framework for developing cell-free regenerative therapies and guiding future experimental validation.

Abstract: Mechanotransduction is how cells convert mechanical stimuli — tension, shear, substrate stiffness, viscoelasticity and confinement — into biochemical and transcriptional signals. Once viewed as a specialty of sensory cells, it is now a general principle of cell biology, spanning scales from single-bond lifetimes to tissue remodeling and timescales from millisecond channel gating to durable epigenetic memory. This review organizes the field into five threads: adhesion and cytoskeletal force sensors; mechanosensitive ion channels; the extracellular matrix as an instructor of cell fate; nuclear mechanotransduction and chromatin remodeling; and the engineering of mechanotransduction. A final section highlights plant mechanobiology, where PIEZO channels and the receptor kinase FERONIA reveal distinct architectures relevant to membrane biophysics and biomolecular condensate biology. Throughout, force acts mainly by directly altering molecular conformation; lipids and membranes are active participants; time-dependent matrix properties often outrank static stiffness; and the genome behaves as a mechanically responsive organelle that records a cell’s mechanical history.

Abstract: Oleanolic acid (OA) is a pentacyclic triterpenoid with broad biological activity and a chemically accessible scaffold that has yielded numerous semisynthetic derivatives. Many of these compounds alter phosphorylation-dependent pathways, including PI3K/AKT/mTOR, AMPK/mTOR, MAPK, JAK/STAT3, NF-κB, and Nrf2 signaling. However, such changes are commonly reported as isolated pathway effects or down-stream responses to cellular stress, with less attention paid to the balance between kinase and phosphatase activities. This review examines OA derivatives at the kinase–phosphatase interface, with emphasis on protein tyrosine phosphatase 1B (PTP1B), re-ceptor tyrosine kinases, EGFR/AKT signaling, and phosphorylation-dependent transi-tions from stress adaptation to cancer cell death. The available evidence links OA and selected derivatives with PTP1B inhibition, receptor-proximal signaling, AKT/mTOR and AMPK/mTOR regulation, stress- and inflammation-related pathways, autophagy, and apoptosis. We also introduce the concept of structure–signaling relationships, in which chemical modification may influence not only potency, but also the point at which a derivative first perturbs the signaling network. Finally, we propose an evidence framework for distinguishing direct target modulation from secondary phosphorylation changes associated with oxidative stress, organelle dysfunction, or advanced cellular injury. Viewing OA derivatives through the kinase–phosphatase interface may provide a more precise basis for their mechanistic evaluation and future development in cancer research.