Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disorder characterized by unexplained fibrosis and limited therapeutic options, highlighting the urgent need for innovative treatments. Hyaluronic acid (HA), which is upregulated in IPF and correlates with disease severity, plays an undefined role in its pathogenesis. Hyaluronic acid synthase 2 (HAS2), a key enzyme in HA production, has an unclear function in IPF progression, particularly regarding its involvement in macrophage polarization. Understanding this mechanism is essential for identifying novel therapeutic targets and developing effective drugs for IPF. The present study investigated the roles of HAS2 and HA in IPF and identified potential therapeutic agents. Transcriptomic analysis revealed HAS2 as a critical IPF‑associated gene in patient samples, bleomycin (BLM)‑induced mouse models, and transforming growth factor β1 (TGF‑β1)‑induced myofibroblasts. Single‑cell RNA sequencing further confirmed the fibroblast‑specific upregulation of HAS2 in fibrotic lungs. Experimental validation showed elevated HAS2 expression and HA accumulation in fibrosis models. HA facilitated macrophage M2 polarization and TGF‑β1 secretion through CD44‑dependent STAT6 activation, with CD44 inhibition blocking this effect. Knockdown of HAS2 in fibroblasts decreased HA release and impaired their ability to promote M2 polarization, suggesting that fibroblast‑derived HA drives this process. High‑throughput virtual screening, coupled with absorption, distribution, metabolism and excretion (ADME) profiling, identified orcinol glucoside (OG) as a potential HAS2 inhibitor, which was validated through surface plasmon resonance, cellular thermal shift assays, and molecular dynamics simulations. OG suppressed HA synthesis in TGF‑β1‑induced and HAS2‑overexpressing myofibroblasts in a dose‑dependent manner, inhibiting M2 polarization induction. In vivo, OG reduced collagen deposition, HA, and TGF‑β1 levels in BLM‑induced fibrotic mice. These findings established HAS2 as a central pathogenic factor in IPF and suggested OG as a promising therapeutic candidate, providing a novel approach for IPF treatment by targeting HA synthesis and macrophage polarization.

The tumour microenvironment of glioblastoma (GBM) as defined by mechanical heterogeneity, hypoxia, and hyaluronic acid (HA)-rich extracellular matrix (ECM), is a highly dynamic milieu which influences tumour progression and therapeutic resistance. Yet, how these cues converge to regulate mechanosensitive pathways in 3D remains poorly understood. Here, we engineered agar-based porous hydrogels functionalized with HA to independently tune stiffness and ECM composition, creating biomimetic 3D niches for GBM cells. The presence of HA coating showed to increase hydrogel stiffness, promote YAP/TAZ nuclear localisation, and elevate total LATS1/2 expression, consistent with Hippo pathway feedback regulation. Over time, however, hypoxic niches emerged that destabilised this feedback, enabling sustained YAP nuclear activity. HA also modulated OCT4 and Sox2 localisation and attenuated HIF-1α nuclear accumulation, indicating that HA also modulates the spatial distribution and nuclear accumulation of HIF-1α. Also, a cooperative regulation through the HA-CD44-CXCR4 axis, showed integrated biochemical and mechanical signals to reinforce YAP/HIF crosstalk. Together, these results reveal a dynamic interplay between ECM stiffness, HA signalling, and hypoxia in shaping YAP/HIF crosstalk and stem-like phenotypes in GBM and establish our hydrogel platform as a powerful tool to dissect and therapeutically exploit these interactions.

Hyaluronic acid chemistry and biomedical material design.

Post-warming culture and single vitrified-warmed blastocyst transfer with hyaluronic acid and prolactin: a randomized controlled trial.

Self-healing hydrogels incorporating hyaluronic acid, poly(Acrylic Acid), and ferric ions for flexible sensing and wound healing.

Combined transplantation of human umbilical cord mesenchymal stem cells and MEEK micrografts in rabbits: A long-term self-controlled study.

Extracellular matrix-mimetic ink for 3D printing and minimally invasive delivery of shape-memory constructs.

Current trend on preparation, properties, and wound healing applications of polysaccharide-based hydrogel patches: A review.

A versatile nanoplatform for enhancing the therapeutic efficacy against low-immunogenic TNBC by inducing immunogenic cell death and MHC-I upregulation.

A multifunctional and ROS response CO-gas delivery platform for spinal cord regeneration.

HYAL2-generated low-molecular-weight hyaluronic acid promotes intervertebral disc degeneration via the CD44/AKT signaling axis.

Skin aging is characterized by a progressive decline in regenerative capacity, primarily driven by fibroblast senescence, oxidative stress, chronic inflammation, and the degradation of type I/III collagen, culminating in an extracellular matrix (ECM) imbalance. Current injectable fillers-such as hyaluronic acid, collagen, and PLLA-provide temporary structural support but fail to address the underlying cellular senescence or restore ECM homeostasis, highlighting the need for regenerative biomaterials. Silk fibroin (SF), a natural protein, self-assembles into a β-sheet-rich scaffold that structurally supports fibroblasts in depositing collagen and elastin, thereby improving the skin's ECM, accelerating wound healing, and promoting tissue regeneration. However, its role in modulating fibroblast senescence and ECM remodeling remains unclear. This study demonstrates that SF provides a suitable microenvironment for the adhesion and proliferation of fibroblasts, reducing the accumulation of SASP factors and facilitating the transition of fibroblasts from a senescent to a functional state. Furthermore, SF improves the skin microenvironment by reducing reactive oxygen species (ROS) and matrix metalloproteinase (MMP) expression through modulation of the ROS-MAPK-AP-1-MMP signal pathway, thereby delaying collagen degradation in aged skin. These findings reveal that SF uniquely rejuvenates fibroblasts and restores ECM homeostasis through a non-inflammatory mechanism, distinguishing it from conventional fillers that rely on inflammatory pathways for collagen induction. This work establishes SF as a next-generation injectable biomaterial with dual targeting of cellular senescence and ECM imbalance, offering a transformative strategy for regenerative dermatology and personalized anti-aging approaches.

Dextran-based microneedle patch Co-delivering safflower polysaccharide and ROS-responsive tetramethylpyrazine micelles for diabetic wound repair.

Cell flocculation and phase-separation support macro-scale tissue slab construction in a scaffold-free manner.

Engineered bacterial outer membrane vesicles enhanced tumor immunotherapy through remodeling tumor stroma and targeted delivery of CD73 siRNA.

Lipid-stabilized ICG nanoaggregates for the photodisruption of vitreous opacities.

3D-printed alginate/gelatin/PCL/hyaluronic acid scaffolds with metal–organic frameworks for quercetin delivery: Improving mechanical properties and cytocompatibility for cartilage tissue engineering applications

Framework nucleic acid-based hydrogel for sequential immune regulation and endogenous TGF-β1 capture in wound healing.

Glucose-hijacked nanobots: Enabling deep tumor penetration via a self-enhanced permeability cascade.

Hyaluronic acid engineered melanin-MOF nanoreactor synergistically remodeling redox and immune homeostasis for targeted acute lung injury therapy.