For decades, the primary cilium was dismissed as a cellular vestige, a tiny hair-like projection that most cells grow and then ignore. A comprehensive review now published in the Journal of Biomedical Science argues that this view is badly outdated. Led by Huan-Tzu Hou, Yu-Ying Chao and Shaw-Jenq Tsai of National Cheng Kung University, the authors synthesize hundreds of studies to reframe the primary cilium as a dynamic, bidirectional interface between environmental sensing and metabolic adaptation. Far from being a passive antenna, the cilium emerges as a signal-processing compartment that receives, integrates, amplifies and relays information controlling glucose and lipid metabolism, calcium dynamics, mitochondrial quality and ultimately cell fate. When this sensory-metabolic axis breaks down, the consequences span cardiovascular disease, infertility, obesity, diabetes, cancer and neurodegeneration.
Structurally, the primary cilium is an elegant piece of cellular engineering. It is anchored by the mother centriole-derived basal body, which during the G0/G1 phase or differentiation docks at the plasma membrane and nucleates a 9+0 microtubule axoneme enclosed in a specialized ciliary membrane. Assembly, maintenance and signaling competence depend on intraflagellar transport, in which IFT-A and IFT-B complexes ride along the axoneme with kinesin-2 and cytoplasmic dynein-2 motors, ferrying cargo in both directions. At the ciliary base, transition fibers and the transition zone act as a selective gate, restricting which receptors, ion channels, transporters and signaling molecules can enter. This selective compartmentalization is what allows the cilium to function as a spatially restricted signaling hub rather than a simple membrane protrusion, concentrating machinery for Hedgehog, G protein-coupled receptor, calcium, receptor tyrosine kinase, TGF-beta and Wnt pathways within a nanometer-scale compartment.
The review’s central conceptual move is to treat the cilium as plastic rather than static. Environmental cues continuously remodel its assembly, length, composition and signaling output. Glucose deprivation, for example, promotes cilium formation in cultured cells mainly through inactivation of the nutrient sensor mTORC1 rather than through autophagy, and intriguingly it increases the proportion of ciliated cells while shortening the cilia themselves, showing that assembly and morphology are regulated separately. Glutamine deprivation tells an even more dramatic story in pancreatic ductal adenocarcinoma: the stress induces a protein called melanophilin, which accumulates at the basal body and drives ciliary regrowth, and the reassembled cilia amplify phospholipase C-gamma1 signaling in a feedforward circuit that promotes metastasis. Endogenous metabolic programs matter too. Local phosphoinositide remodeling at the centrosome recruits tau tubulin kinase 2, triggering removal of CP110, a cap that blocks axoneme extension, while cholesterol accessibility within the ciliary membrane modulates Smoothened activity in the Hedgehog pathway. Conversely, activation of SREBP1-driven lipogenesis and fatty acid synthesis suppresses ciliogenesis, in part by distorting vesicular trafficking.
Mechanical forces provide a second major class of inputs. In renal epithelial cells, urinary flow bends the apical cilium and activates calcium signaling through the polycystin-1 and polycystin-2 complex, proteins whose disruption causes polycystic kidney disease. Cilia-mediated flow sensing also regulates shear-dependent apical endocytosis in proximal tubules, linking mechanotransduction to reabsorptive function. In vascular endothelium the picture is context-dependent: cilia are retained under static or disturbed-flow conditions, whereas sustained laminar shear promotes ciliary shortening or disassembly, altering the cell’s capacity for cilia-dependent nitric oxide production. In bone, cilia deflect under dynamic fluid flow and are required for osteogenic responses and flow-induced calcium deposition in osteoblasts; in cartilage, they mediate compression-induced ATP release that regulates the extracellular matrix. Even substrate stiffness matters, since rigid matrices can suppress ciliogenesis through actomyosin tension-driven nuclear deformation and keratin-associated protein upregulation.
Oxygen tension adds a third layer of regulation. The von Hippel-Lindau protein, an E3 ubiquitin ligase that degrades HIF-alpha, localizes to the cilium and basal body, where it supports microtubule stability and cilium maintenance; loss of pVHL impairs ciliogenesis in renal-derived cells, and restoring it rescues cilium formation. Under hypoxia, HIF-2alpha can interact with the transport protein IFT88 to promote ciliogenesis and influence MEK/ERK signaling. The authors are careful to note that cilia are not universal hypoxia sensors but rather context-dependent platforms connecting oxygen-responsive signaling to localized ciliary regulation. Intracellular microRNAs form a distinct regulatory class: miR-129-3p promotes ciliogenesis by targeting CP110 and modulating actin dynamics, miR-669a-5p promotes ciliary elongation, and miR-182 and miR-183 are essential for maintaining the cone photoreceptor outer segments, which are highly specialized primary cilia required for vision.
Nowhere is the metabolic role of cilia more vivid than in the pancreatic islet. Beta-cell cilia compartmentalize receptors that regulate hormone secretion: insulin stimulation recruits insulin receptor isoform A to the cilium, and disrupting ciliary integrity attenuates downstream PI3K/Akt signaling. In Bbs4-deficient mice, ciliary dysfunction delays glucose clearance and impairs insulin secretion. Cilia-localized GPCRs add further control: free fatty acid receptor 4 and prostaglandin E2 receptor 4 enhance glucose-stimulated insulin secretion through cAMP-dependent pathways, while somatostatin receptor 3, activated by delta-cell somatostatin, lowers ciliary cAMP and triggers cilia-restricted calcium signaling that drives GLI2 nuclear translocation, tying GPCR signaling to the Hedgehog axis that maintains beta-cell identity. Recent work even identified endogenous GLP-1 receptors on beta-cell cilia, with loss of cilia blunting liraglutide-induced cAMP, calcium and insulin secretion. Endothelial cilia support the islet too, facilitating VEGFR2 internalization and downstream ERK and Akt signaling needed for vascularization and glucose delivery.
Lipid metabolism reveals the cilium’s capacity to integrate opposing signals. Cilium-dependent Hedgehog signaling suppresses the adipogenic transcriptional program, inhibiting fat cell differentiation, while lipid-raft organization at the ciliary base supports Akt-dependent adipogenesis and omega-3 fatty acid activation of ciliary FFAR4 initiates it. In muscle and brown fat, cilium-dependent Smoothened-calcium signaling activates AMPK, promoting glucose uptake and Warburg-like reprogramming. In renal epithelial cells, cilia couple extracellular cues to LKB1-AMPK signaling and mTORC1 suppression, and they sense fluid flow to promote lipophagy, mobilizing fatty acids from lipid droplets for mitochondrial beta-oxidation and ATP production. Prolonged shear stress promotes cilium-dependent mitochondrial biogenesis, increasing mitochondrial mass, DNA content, oxidative phosphorylation and ATP output through AMPK-PGC1alpha and TFEB-dependent programs, while decreased IFT88 expression with ciliary shortening is associated with impaired mitochondrial function in cisplatin-induced tubular injury.
Disease connections run deep. In the vasculature, endothelial cilia are enriched at arterial branch points where atherosclerosis preferentially develops, and loss of endothelial cilia promotes inflammatory activation and accelerates plaque progression; lipid droplet accumulation in endothelial cells sequesters palmitic acid, suppresses S-palmitoylation of ciliary proteins and impairs ciliogenesis. In reproduction, endometrial stromal cilia mediate Hedgehog-dependent epithelial-stromal communication during decidualization, and in endometriosis the cilia are shorter and decidualization responses reduced, with TGF-beta1 suppressing ciliogenesis by downregulating KIF3B. Trophoblast cilia are shortened in preeclamptic placentas, where inflammatory cytokines impair Hedgehog signaling and motility, and deleterious variants in the dynein-2 heavy chain gene DYNC2H1 have been identified in euploid recurrent pregnancy loss. In obesity, the melanocortin 4 receptor signals from hypothal neuronal cilia to suppress appetite, and MC4R-bearing cilia shorten with aging and overnutrition, reducing melanocortin sensitivity, energy expenditure and thermogenesis. Human type 2 diabetic islets show shortened beta-cell cilia and reduced beta-cell to delta-cell contacts, while classical ciliopathies such as Bardet-Biedl syndrome combine obesity with BBSome-dependent defects in mitochondrial dynamics.
Cancer adds a final, paradoxical dimension. Many tumors lose primary cilia as cells re-enter the cell cycle, yet under genotoxic or nutrient stress some cancer cells reassemble or elongate them as an adaptive survival strategy. Cisplatin-resistant pancreatic cancer cells regrow cilia through DNA damage signaling, and disrupting ciliogenesis resensitizes them; in glioblastoma, blocking ciliogenesis increases sensitivity to temozolomide and radiation. In neurodegeneration, LRRK2 mutations in Parkinson’s disease block ciliogenesis and cilia-dependent Sonic hedgehog signaling, while loss of cilia impairs clearance of damaged mitochondria in dopaminergic neurons; in Alzheimer’s models, neuronal cilia near amyloid plaques are shortened. The authors emphasize that ciliary remodeling is neither uniformly protective nor pathogenic, and that defining the cellular and environmental contexts in which it helps or harms will be essential. With live ciliary signaling reporters, tissue-specific manipulation models and spatial multi-omics now emerging, the field stands poised to move from describing these organelles to decoding, and perhaps therapeutically rewiring, the sensory-metabolic conversations they conduct.
Subject of Research: The role of primary cilia as sensory organelles and metabolic signaling hubs in physiology and disease
Article Title: Primary cilium as a sensory organelle and metabolic hub in health and diseases
Article References: Hou, H.-T., Chao, Y.-Y., Li, J.-N., Peng, I.-C., Lin, T.-C., Chiu, W.-T., Wang, C.-Y., & Tsai, S.-J. (2026). Primary cilium as a sensory organelle and metabolic hub in health and diseases. Journal of Biomedical Science, 33(1), Article 92. https://doi.org/10.1186/s12929-026-01291-6
Image Credits: AI Generated
DOI: 10.1186/s12929-026-01291-6
Keywords: primary cilium, ciliogenesis, metabolism, Hedgehog signaling, mTORC1, mechanotransduction, mitochondria, diabetes, obesity, ciliopathies, cancer, neurodegeneration
