Lin Chen

Genetic manipulation technologies (GMTs) serve as potent instruments for elucidating the molecular and cellular mechanisms that underly both physiological and pathological processes. However, the increasing recognition of the cellular heterogeneity in terms of their spatial distribution, cellular subtypes, and functional states in complex tissues, has posed new challenges to the applicability and precision of these technologies. While current GMTs facilitate precise genetic interventions at the molecular level, their capacity for achieving cell-specific genetic regulation remains constrained. In this context, we utilize research on fibroblast growth factors (FGFs)/FGF receptors (FGFRs) signaling in osteoarthritis (OA) as a case to demonstrate the technical limitations faced by existing GMTs. To address these constraints, we propose a conceptual framework termed Materialogenetics, which integrates advances in biomaterials science with genetic manipulation approaches. Advanced biomaterials with active-targeting and stimuli-responsive properties have been widely explored in disease diagnosis and therapy. When combined with GMTs, these materials can theoretically greatly improve cell-specific and spatiotemporally controlled genetic manipulation at both molecular and cellular levels. Moreover, biomaterial-assisted genetic manipulation offers several practical advantages, including cost-effectiveness, operational simplicity, and a high degree of tunability, rendering the platform highly adaptable to a wide range of research contexts. Collectively, Materialogenetics establishes a conceptual framework that bridges the fields of materials science and genetics, representing a versatile and promising platform for achieving precise genetic manipulation in complex biological systems.

Dysregulated cholesterol metabolism has been implicated in several aging‐associated disorders, including osteoarthritis (OA). 3‐Hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR) is the key enzyme in cholesterol biosynthesis, but the role of HMGCR in OA and the underlying mechanism remain unclear. In this study, we found that HMGCR ⁺ fibroblasts (FLSs) were significantly increased in the knee synovium of OA patients and OA mice. Elevated expression of HMGCR in synovial FLSs was positively correlated with cellular senescence and OA progression. The inhibition of HMGCR reversed cellular senescence of FLSs induced by TNF‐α in vitro. Additionally, the HMGCR‐mediated cholesterol biosynthetic pathway contributed to cellular senescence. Targeted inhibition of HMGCR in synovial FLSs via intra‐articular adeno‐associated virus delivery effectively reversed cellular senescence of FLSs and mitigated synovitis, cartilage degradation, and pain behaviors in OA mice. Mechanistically, the phosphorylation of AKT1 at Ser473 enhanced its binding to Lys140 of Insig1, facilitating AKT1–Insig1 complex formation. The activation of AKT1 induced the phosphorylation of Insig1 at Ser189 and the dissociation of Insig1 from sterol regulatory element‑binding protein cleavage‑activating protein (SCAP), which contributed to HMGCR transcription and cellular senescence of FLSs. Collectively, our study reveals a novel mechanism of HMGCR‐driven cellular senescence of FLSs in OA, which highlights HMGCR as a promising therapeutic target for OA.

Intervertebral disc degeneration (IDD) is a common cause of low back pain that causes significant debilitation. The intricate mechanisms governing intervertebral disc homeostasis are substantially impacted by cellular senescence, which plays crucial roles in both pathological and physiological contexts. In this review, we provide a comprehensive overview of cellular senescence in the pathogenesis of IDD. Specifically, we summarize the merits and limitations of the methodologies utilized in prior investigations to determine cellular senescence and the potential regulatory mechanisms underlying it in the progression of IDD. Furthermore, we describe therapeutic strategies that aim to inhibit cellular senescence, which may alleviate the pathogenesis of IDD. At last, we discuss the challenges and prospects of translational research on targeting cellular senescence in IDD treatment.

Background: Mild cognitive impairment (MCI), a condition that falls somewhere between normal aging and severe cognitive dysfunction (e.g., Alzheimer’s disease), is a common manifestation of the neurocognitive function decline that seniors encounter as they age. The fundamental processes causing its beginning are still not well understood yet. Methods: We employed aged (18-month-old) male C57BL/6J mice, including astrocyte-specific Pantothenate kinases 4 (PANK4) conditional knockout (Pank4 ^f/f ;Gfap-Cre, Pank4-CKO) mice. Cognitive function was assessed using the Barnes maze, Y-maze (spatial novelty preference, spontaneous alternation), novel object recognition (NOR) test, and open field test (OFT). Hippocampal PANK4 localization was analyzed via immunofluorescence (IF) and subcellular fractionation/western blotting (WB). Cuproptosis markers (FDX1, LIAS, DLAT), copper transporters (ATP7A, ATP7B, SLC31A1), and copper content (ICP-MS) were quantified in hippocampal tissue. In vitro studies used LPS-stimulated primary astrocytes for RNA-seq and qPCR validation. Results: Aged wild-type (18M+WT) mice exhibited specific deficits in Barnes maze retention and reversal learning, indicative of mild cognitive impairment, while Pank4-CKO mice showed significant rescue. We discovered a novel age-dependent nuclear accumulation of PANK4 in hippocampal cells, which was absent in Pank4-CKO mice. Aged hippocampi displayed upregulated pro-cuproptotic factors (FDX1, LIAS) and reduced DLAT, alongside decreased expression of the copper exporter ATP7A, ATP7B, SLC31A1 and increased copper accumulation. Astrocyte-specific Pank4 knockout reversed these changes: it suppressed FDX1/LIAS upregulation, restored ATP7B expression and DLAT levels, and normalized hippocampal copper content. In vitro , LPS-induced neuroinflammation triggered PANK4 nuclear translocation and selectively downregulated Atp7b expression in astrocytes. Small interfering RNA (siRNA)-mediated knockdown of Pank4 significantly upregulated Atp7b expression. Conclusion: This study identifies a novel pathological mechanism in age-related MCI: the nuclear accumulation of PANK4 in hippocampal exacerbates cuproptosis susceptibility by specifically impairing ATP7B-dependent copper efflux, leading to copper overload. Astrocyte-specific PANK4 ablation mitigates these effects, highlighting PANK4 as a potential therapeutic target for preventing or treating age-associated cognitive decline.

Lactate accumulation is a hallmark and contributing factor of intervertebral disc degeneration (IVDD), while the role of protein lactylation caused by lactate accumulation in IVDD remains unclear. Via metabolomics, single-cell RNA-sequencing analysis, and lactylation proteomics, we reveal the lactylome landscape in IVDD and identified superoxide dismutase 1 (SOD1) lactylation at lysine 123 (SOD1^K123la) as crucial for IVDD aggravation. Using in vitro site-directed mutagenesis, in vivo generation of SOD1^K123R mutant male rats, and in silico molecular dynamics simulations, we find that SOD1^K123la alters SOD1 conformation and impairs its enzymatic activity, and induces oxidative damage, and activates p53 pathway in nucleus pulposus cells (NPCs). Notably, we identify a small molecule ZL-01 that inhibits SOD1^K123la. NPC-targeted delivery of ZL-01 via collagen type II-targeted peptide-modified extracellular vesicles alleviated IVDD in male rats. Together, these findings clarify the mechanism by which SOD1^K123la promotes IVDD aggravation and provide a promising therapeutic strategy for IVDD.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, affecting a large population and exerting a substantial burden on the healthcare system worldwide. Conventional therapeutic approaches, including conservative management and surgical intervention, predominantly focus on relieving pain and symptoms rather than targeting the underlying pathophysiological mechanisms, which often leads to limited long‐term effectiveness. With advancements in nanotechnology and regenerative medicine, nanomaterial‐assisted therapies introduce a new paradigm for IVDD treatment. Preclinical studies demonstrate promising disease‐modifying outcomes using these innovative approaches. In this review, the latest developments in nanomaterials, particularly nanoparticles and nanocomposite hydrogels, within the context of IVDD treatment, are summarized, with emphasis on the enhanced biological performance achieved by engineering approaches such as composition regulation, structural design, and surface modification. In addition, the current advances are outlined in understanding the therapeutic mechanisms of nanomaterials for the treatment of IVDD, while addressing the opportunities and challenges associated with their development and clinical translation.

Calcific aortic valve disease (CAVD) is a highly prevalent disease that leads to heart failure. However, the pathogenesis of CAVD remains poorly understood, and the disease currently lacks medicinal treatment. In this study, utilizing a high‐phosphate‐diet‐induced valvular calcification model in conjunction with single‐cell profiling and genetic tracing, two subpopulations of Prrx1 ⁺ Acta2 ⁻ valve interstitial cells (VICs) are identified that underwent osteogenic differentiation. Mechanistically, elevated phosphate suppresses the expression of vitamin D metabolism genes primarily in VICs and response genes in immune cells, leading to local activation of CD8 ⁺ T cells, macrophages, and Prox1 ⁺ endothelial cells in the valve. It is further shown that inflammatory cytokines and phosphate ions synergistically induced VIC osteogenic differentiation via extracellular regulated protein kinases (ERK) signaling. Administration of active vitamin D but not the inactive form suppressed inflammation and mitigated valvular calcification. Moreover, the VIC subpopulations undergoing osteogenic differentiation, suppressed expression of vitamin D metabolism and response genes, and inflammation are also observed in valve samples from patients with CAVD. This study reveals the cellular and molecular basis for valvular calcification and identifies active vitamin D as a potential drug to prevent CAVD development.