LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.

Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential.

IκB kinase-α coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy.

Activation of the IκB kinase (IKK) complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF-κB has remained elusive. Here, analysis of IKK-dependent substrates in CRC cells after UV treatment revealed that phosphorylation of BRD4 by IKK-α is required for its chromatin-binding at target genes upon DNA damage. Moreover, IKK-α induces the NF-κB-dependent transcription of the cytokine LIF, leading to STAT3 activation, association with BRD4 and recruitment to specific target genes. IKK-α abrogation results in defective BRD4 and STAT3 functions and consequently irreparable DNA damage and apoptotic cell death upon different stimuli. Simultaneous inhibition of BRAF-dependent IKK-α activity, BRD4, and the JAK/STAT pathway enhanced the therapeutic potential of 5-fluorouracil combined with irinotecan in CRC cells and is curative in a chemotherapy-resistant xenograft model. Finally, coordinated expression of LIF and IKK-α is a poor prognosis marker for CRC patients. Our data uncover a functional link between IKK-α, BRD4, and JAK/STAT signaling with clinical relevance.

Autocrine Loop Involving IL-6 Family Member LIF, LIF Receptor, and STAT4 Drives Sustained Fibroblast Production of Inflammatory Mediators.

Fibroblasts are major contributors to and regulators of inflammation and dominant producers of interleukin-6 (IL-6) in inflammatory diseases like rheumatoid arthritis. Yet, compared to leukocytes, the regulation of inflammatory pathways in fibroblasts is largely unknown. Here, we report that analyses of genes coordinately upregulated with IL-6 pointed to STAT4 and leukemia inhibitory factor (LIF) as potentially linked. Gene silencing revealed that STAT4 was required for IL-6 transcription. STAT4 was recruited to the IL-6 promoter after fibroblast activation, and LIF receptor (LIFR) and STAT4 formed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation. Importantly, a positive feedback loop involving autocrine LIF, LIFR, and STAT4 drove sustained IL-6 transcription. Besides IL-6, this autorine loop also drove the production of other key inflammatory factors including IL-8, granulocyte-colony stimulating factor (G-CSF), IL-33, IL-11, IL-1α, and IL-1ß. These findings define the transcriptional regulation of fibroblast-mediated inflammation as distinct from leukocytes.

IL-6 promotes tumor growth through immune evasion but is dispensable for cachexia.

Various cytokines have been implicated in cancer cachexia. One such cytokine is IL-6, deemed as a key cachectic factor in mice inoculated with colon carcinoma 26 (C26) cells, a widely used cancer cachexia model. Here we tested the causal role of IL-6 in cancer cachexia by knocking out the IL-6 gene in C26 cells. We found that the growth of IL-6 KO tumors was dramatically delayed. More strikingly, while IL-6 KO tumors eventually reached the similar size as wild-type tumors, cachexia still took place, despite no elevation in circulating IL-6. In addition, the knockout of leukemia inhibitory factor (LIF), another IL-6 family cytokine proposed as a cachectic factor in the model, also affected tumor growth but not cachexia. We further showed an increase in the infiltration of immune cell population in the IL-6 KO tumors compared with wild-type controls and the defective IL-6 KO tumor growth was rescued in immunodeficient mice while cachexia was not. Thus, IL-6 promotes tumor growth by facilitating immune evasion but is dispensable for cachexia.

Engineered interleukin-6-derived cytokines recruit artificial receptor complexes and disclose CNTF signaling via the OSMR.

Ciliary neurotrophic factor (CNTF) activates cells via the non-signaling α-receptor CNTF receptor (CNTFR) and the two signaling ß-receptors glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR). The CNTF derivate, Axokine, was protective against obesity and insulin resistance, but clinical development was halted by the emergence of CNTF antibodies. The chimeric cytokine IC7 used the framework of interleukin (IL-)6 with the LIFR-binding site from CNTF to activate cells via IL-6R:gp130:LIFR complexes. Similar to CNTF/Axokine, IC7 protected mice from obesity and insulin resistance. Here, we developed CNTF-independent chimeras that specifically target the IL-6R:gp130:LIFR complex. In GIL-6 and GIO-6, we transferred the LIFR binding site from LIF or OSM to IL-6, respectively. While GIO-6 signals via gp130:IL-6R:LIFR and gp130:IL-6R:OSMR complexes, GIL-6 selectively activates the IL-6R:gp130:LIFR receptor complex. By re-evaluation of IC7 and CNTF, we discovered the Oncostatin M receptor (OSMR) as an alternative non-canonical high-affinity receptor leading to IL-6R:OSMR:gp130 and CNTFR:OSMR:gp130 receptor complexes, respectively. The discovery of OSMR as an alternative high-affinity receptor for IC7 and CNTF designates GIL-6 as the first truly selective IL-6R:gp130:LIFR cytokine, whereas GIO-6 is a CNTF-free alternative for IC7.

Glycolytic Pfkp acts as a Lin41 protein kinase to promote endodermal differentiation of embryonic stem cells.

Unveiling the principles governing embryonic stem cell (ESC) differentiation into specific lineages is critical for understanding embryonic development and for stem cell applications in regenerative medicine. Here, we establish an intersection between LIF-Stat3 signaling that is essential for maintaining murine (m) ESCs pluripotency, and the glycolytic enzyme, the platelet isoform of phosphofructokinase (Pfkp). In the pluripotent state, Stat3 transcriptionally suppresses Pfkp in mESCs while manipulating the cells to lift this repression results in differentiation towards the ectodermal lineage. Pfkp exhibits substrate specificity changes to act as a protein kinase, catalyzing serine phosphorylation of the developmental regulator Lin41. Such phosphorylation stabilizes Lin41 by impeding its autoubiquitination and proteasomal degradation, permitting Lin41-mediated binding and destabilization of mRNAs encoding ectodermal specification markers to favor the expression of endodermal specification genes. This provides new insights into the wiring of pluripotency-differentiation circuitry where Pfkp plays a role in germ layer specification during mESC differentiation.

Novel Two-Terminal Synapse/Neuron Based on an Antiferroelectric Hafnium Zirconium Oxide Device for Neuromorphic Computing.

Functionally diverse devices with artificial neuron and synapse properties are critical for neuromorphic systems. We present a two-terminal artificial leaky-integrate-fire (LIF) neuron based on 6 nm Hf0.1Zr0.9O2 (HZO) antiferroelectric (AFE) thin films and develop a synaptic device through work function (WF) engineering. LIF neuron characteristics, including integration, firing, and leakage, are achieved in W/HZO/W devices due to the accumulated polarization and spontaneous depolarization of AFE HZO films. By engineering the top electrode with asymmetric WFs, we found that Au/Ti/HZO/W devices exhibit synaptic weight plasticity, such as paired-pulse facilitation and long-term potentiation/depression, achieving >90% accuracy in digit recognition within constructed artificial neural network systems. These findings suggest that AFE HZO capacitor-based neurons and WF-engineered artificial synapses hold promise for constructing efficient spiking neuron networks and artificial neural networks, thereby advancing neuromorphic computing applications based on emerging AFE HZO devices.

Interfacial Layers with Desolvation Function Induced Stable Deposition of Lithium Metal for Long-Cycling Lithium Metal Batteries.

The unstable solid electrolyte interface (SEI) formed by uncontrollable electrolyte degradation, which leads to dendrite growth and Coulombic efficiency decay, hinders the development of Li metal anodes. A controllable desolvation process is essential for the formation of stable SEI and improved lithium metal deposition behavior. Here, we show a functional artificial interface protective layer comprised of chondroitin sulfate-reduced graphene oxide (CrG), on which polar functional groups are distributed to effectively reduce the energy barrier for desolvation of Li+ and effectively alienate solvent molecules to avoid solvent involvement in SEI formation, thus promoting the formation of a LiF-rich SEI. Consequently, stable Coulombic efficiencies of 98.4% were achieved after 500 cycles in a Li//Cu cell. Moreover, the LiFePO4 full cells achieve steady circulation (470 cycles at 80%, 1 C) with a negative/positive electrode capacity ratio of 2.87. Our multifunctional artificial interface protective layer provides a new way to advance Li metal batteries.

Roles of leukemia inhibitory factor receptor in cancer.

Leukemia inhibitory factor receptor (LIFR), in complex with glycoprotein 130 (gp130) as the receptor for leukemia inhibitory factor (LIF), can bind to a variety of cytokines and subsequently activate a variety of signaling pathways, including Janus kinase/signal transducer and activator of transcription 3. LIF, the most multifunctional cytokines of the interleukin-6 family acts as both a growth factor and a growth inhibitor in different types of tumors. LIF/LIFR signaling regulates a broad array of tumor-related processes including proliferation, apoptosis, migration, invasion. However, due to the activation of different signaling pathways, opposite regulatory effects are observed in certain tumor cells. Therefore, the role of LIFR in human cancers varies across different tumor and tissue, despite their recognized value in tumor treatment and prognosis observation is affirmed. Given its aberrant expression in numerous tumor cells and crucial regulatory function in tumorigenesis and progression, LIFR is considered as a promising targeted therapeutic agent. This review provides an overview of LIFR's initiating signaling pathway function as a cytokine receptor and summarize the current literature on the role of LIFR in cancer and its possible use in therapy.

Antagonist anti-LIF antibody derived from naive human scFv phage library inhibited tumor growth in mice.

BACKGROUND: Leukemia inhibitory factor (LIF) is a multifunctional member of the IL-6 cytokine family that activates downstream signaling pathways by binding to the heterodimer consisting of LIFR and gp130 on the cell surface. Previous research has shown that LIF is highly expressed in various tumor tissues (e.g. pancreatic cancer, breast cancer, prostate cancer, and colorectal cancer) and promotes cancer cell proliferation, migration, invasion, and differentiation. Moreover, the overexpression of LIF correlates with poor clinicopathological characteristics. Therefore, we hypothesized that LIF could be a promising target for the treatment of cancer. In this work, we developed the antagonist antibody 1G11 against LIF and investigated its anti-tumor mechanism and its therapeutic efficacy in mouse models. RESULTS: A series of single-chain variable fragments (scFvs) targeting LIF were screened from a naive human scFv phage library. These scFvs were reconstructed in complete IgG form and produced by the mammalian transient expression system. Among the antibodies, 1G11 exhibited the excellent binding activity to human, cynomolgus monkey and mouse LIF. Functional analysis demonstrated 1G11 could block LIF binding to LIFR and inhibit the intracellular STAT3 phosphorylation signal. Interestingly, 1G11 did not block LIF binding to gp130, another LIF receptor that is involved in forming the receptor complex together with LIFR. In vivo, intraperitoneal administration of 1G11 inhibited tumor growth in CT26 and MC38 models of colorectal cancer. IHC analysis demonstrated that p-STAT3 and Ki67 were decreased in tumor tissue, while c-caspase 3 was increased. Furthermore, 1G11 treatment improves CD3+, CD4 + and CD8 + T cell infiltration in tumor tissue. CONCLUSIONS: We developed antagonist antibodies targeting LIF/LIFR signaling pathway from a naive human scFv phage library. Antagonist anti-LIF antibody exerts antitumor effects by specifically reducing p-STAT3. Further studies revealed that anti-LIF antibody 1G11 increased immune cell infiltration in tumor tissues.

Unveiling the Mystery of LiF within Solid Electrolyte Interphase in Lithium Batteries.

Over the past decades, significant advances have been made in lithium-ion batteries. However, further requirement on the electrochemical performance is still a powerful motivator to improve battery technology. The solid electrolyte interphase (SEI) is considered as a key component on negative electrode, having been proven to be crucial for the performance, even in safety of batteries. Although numerous studies have focused on SEI in recent years, its specific properties, including structure and composition, remain largely unclear. Particularly, LiF, a common and important component in SEI, has sparked debates among researchers, resulting in divergent viewpoints. In this review, the recent research findings on SEI and delve into the characteristics of the LiF component is aim to consolidated. The cause of SEI formation and the evolution of SEI models is summarized. The distinctive properties of SEI generated on various negative electrodes is further discussed, the ongoing scholarly controversy surrounding the function of LiF within SEI, and the specific physicochemical properties about LiF and its synergistic effect in heterogeneous components. The objective is to facilitate better understanding of SEI and the role of the LiF component, ultimately contributing to the development of Li batteries with enhanced electrochemical performance and safety for battery communities.

LiF-Rich Solid Electrolyte Interphase Formation by Establishing Sacrificial Layer on the Separator.

The formation of a stable solid electrolyte interphase (SEI) layer is crucial for enhancing the safety and lifespan of Li metal batteries. Fundamentally, a homogeneous Li+ behavior by controlling the chemical reaction at the anode/electrolyte interface is the key to establishing a stable SEI layer. However, due to the highly reactive nature of Li metal anodes (LMAs), controlling the movement of Li+ at the anode/electrolyte interface remains challenging. Here, an advanced approach is proposed for coating a sacrificial layer called fluorinated self-assembled monolayer (FSL) on a boehmite-coated polyethylene (BPE) separator to form a stable SEI layer. By leveraging the strong affinity between the fluorine functional group and Li+, the rapid formation of a LiF-rich SEI layer in the cell production and early cycling stage is facilitated. This initial stable SEI formation promotes the subsequent homogeneous Li+ flux, thereby improving the LMA stability and yielding an enhanced battery lifespan. Further, the mechanism behind the stable SEI layer generation by controlling the Li+ dynamics through the FSL-treated BPE separator is comprehensively verified. Overall, this research offers significant contributions to the energy storage field by addressing challenges associated with LMAs, thus highlighting the importance of interfacial control in achieving a stable SEI layer.

FGF2, LIF, and IGF-1 supplementation improves mouse oocyte in vitro maturation via increased glucose metabolism†.

Chemically defined oocyte maturation media supplemented with FGF2, LIF, and IGF-1 (FLI medium) enabled significantly improved oocyte quality in multiple farm animals, yet the molecular mechanisms behind such benefits were poorly defined. Here, we first demonstrated that FLI medium enhanced mouse oocyte quality assessed by blastocyst formation after in vitro fertilization and implantation and fetal development after embryo transfer. We then analyzed the glucose concentrations in the spent media; reactive oxygen species concentrations; mitochondrial membrane potential; spindle morphology in oocytes; and the abundance of transcripts of endothelial growth factor-like factors, cumulus expansion factors, and glucose metabolism-related genes in cumulus cells. We found that FLI medium enabled increased glucose metabolism through glycolysis, pentose phosphate pathway, and hexosamine biosynthetic pathway, as well as more active endothelial growth factor-like factor expressions in cumulus cells, resulting in improved cumulus cell expansion, decreased spindle abnormality, and overall improvement in oocyte quality. In addition, the activities of MAPK1/3, PI3K/AKT, JAK/STAT3, and mTOR signaling pathways in cumulus cells were assessed by the phosphorylation of MAPK1/3, AKT, STAT3, and mTOR downstream target RPS6KB1. We demonstrated that FLI medium promoted activations of all these signaling pathways at multiple different time points during in vitro maturation.

Investigation of interactions between biological thiols and gold nanoparticles by capillary electrophoresis with laser-induced fluorescence.

Biological thiols spontaneously form a stable Au-S dative bond with gold nanoparticles (AuNP) that might be used for their selective extraction and enrichment in biological samples. In this work, interactions of selected biological thiols (glutathione, cysteine, homocysteine [Hcys], cysteamine [CA], and N-acetylcysteine) with AuNP stabilized by different capping agents (citrate, Tween 20, Brij 35, CTAB, SDS) were investigated by UV-Vis spectroscopy and capillary electrophoresis with laser-induced fluorescence. Spectrophotometric measurements showed aggregation of Hcys and CA with AuNP. In contrast, it was confirmed by CE-LIF that biological thiols were adsorbed to all types of AuNP. Citrate-capped AuNP were selected for AuNP-based extraction of biological thiols from exhaled breath condensate (EBC). Dithiothreitol was utilized for desorption of biological thiols from the AuNP surface, which was followed by derivatization with eosin-5-maleimide and CE-LIF analysis. AuNP-based extraction increased the sensitivity of CE-LIF analysis; however, further optimization of methodology is necessary for accurate quantification of biological thiols in EBC.

Microscale Chaotic Mixing as a Driver for Chemical Reactions in Porous Media.

Mixing-induced reactions play a key role in a large range of biogeochemical and contaminant transport processes in the subsurface. Fluid flow through porous media was recently shown to exhibit chaotic mixing dynamics at the pore scale, enhancing microscale concentration gradients and controlling mixing rates. While this phenomenon is likely ubiquitous in environmental systems, it is not known how it affects chemical reactions. Here, we use refractive index matching and laser-induced fluorescence imaging of a bimolecular redox reaction to investigate the consequence of pore scale chaotic mixing on the reaction rates. The overestimation of measured reaction rates by the classical macrodispersion model highlights the persistence of incomplete mixing on the pore scale. We show that the reaction product formation is controlled by microscale chaotic mixing, which induces an exponential increase of the mixing interface and of the reaction rates. We derive a reactive transport model that captures experimental results and predicts that chaotic mixing has a first order control on reaction rates across a large range of time scales and Péclet and Damköhler numbers. These findings provide a new framework for understanding, assessing, and predicting mixing-induced reactions and their role on the fate and mobility of environmental compounds in natural porous media.

Utilizing Laser-Induced Fluorescence to Evaluate the Efficiency of Carbon Dioxide and Diode Lasers in Dentin Sealing after Tooth Preparation: An in-vitro Study.

Adhesive dentistry has made it feasible to design restorations with high aesthetic qualities and little invasiveness. However, the freshly cut dentin after the tooth preparation needs to be sealed to prevent its contaminations, bacterial leakage, and hypersensitivity. Consequently, the immediate dentin sealing (IDS) method has been advised. This study examines different dentinal tubule sealing methods via CO2 laser, diode laser (980-nm) and a two-step self-etch adhesive system applied directly to the fresh cut dentin preceding the placement of the provisional phase. The sealing efficiency of each laser and bond system was evaluated based on the laser-induced fluorescence (LIF) properties and image analysis by scanning electron microscopy. Moreover, the obtained LIF spectra were evaluated using partial least square progression. A two-step adhesive containing a high concentration of S-PRG fillers produced a thick layer that was not perfectly uniform at all sites due to uneven filler distribution in the bond with totally and partially closed dentinal tubules. However, the peaks of the LIF spectra dropped after applying laser because of its sealing effectiveness. Accordingly, CO2 and diode lasers have strong evidence in dentinal tubule sealing and a definitive treatment modality for dentinal hypersensitivity. Moreover, IDS with an adhesive system is superior in occluding dentinal tubules in a biomimetic manner based on its filler content and bioactive properties.

Discovery of YS-1 as a cell line of gastric inflammatory cancer-associated fibroblasts.

BACKGROUND: Inflammatory cancer-associated fibroblasts (iCAFs) was first identified by co-culture of pancreatic stellate cells and tumor organoids. The key feature of iCAFs is IL-6high/αSMAlow. We examine this phenomenon in gastric cancer using two cell lines of gastric fibroblasts (HGF and YS-1). METHODS AND RESULTS: HGF or YS-1 were co-cultured with MKN7 (a gastric adenocarcinoma cell line) in Matrigel. IL-6 protein levels in the culture supernatant were measured by ELISA. The increased production of IL-6 was not observed in any of the combinations. Instead, the supernatant of YS-1 exhibited the higher levels of IL-6. YS-1 showed IL-6high/αSMA (ACTA2)low in real-time PCR, mRNA-seq and immunohistochemistry. In mRNA-seq, iCAFs-associated genes and signaling pathways were up-regulated in YS-1. No transition to myofibroblastic phenotype was observed by monolayer culture, or the exposure to sonic hedgehog (SHH) or TGF-ß. YS-1 conditioned medium induced changes of morphology and stem-ness/differentiation in NUGC-3 (a human gastric adenocarcinoma cell line) and UBE6T-15 (a human bone marrow-derived mesenchymal stem cell line). CONCLUSIONS: YS-1 is a stable cell line of gastric iCAFs. This discovery will promote further research on iCAFs for many researchers.

Identification and genetic validation of leukemia inhibitory factor super-enhancers in acute respiratory distress syndrome and lung cancer.

Super-enhancers play prominent roles in driving robust pathological gene expression, but they are hidden in human genome at noncoding regions, making them difficult to explore. Leukemia inhibitory factor (LIF) is a multifunctional cytokine crucially involved in acute respiratory distress syndrome (ARDS) and lung cancer progression. However, the mechanisms governing LIF regulation in disease contexts remain largely unexplored. In this study, we observed elevated levels of LIF in the bronchoalveolar lavage fluid (BALF) of patients with sepsis-related ARDS compared to those with nonsepsis-related ARDS. Furthermore, both basal and LPS-induced LIF expression were under the control of super-enhancers. Through analysis of H3K27Ac ChIP-seq data, we pinpointed three potential super-enhancers (LIF-SE1, LIF-SE2, and LIF-SE3) located proximal to the LIF gene in cells. Notably, genetic deletion of any of these three super-enhancers using CRISPR-Cas9 technology led to a significant reduction in LIF expression. Moreover, in cells lacking these super-enhancers, both cell growth and invasion capabilities were substantially impaired. Our findings highlight the critical role of three specific super-enhancers in regulating LIF expression and offer new insights into the transcriptional regulation of LIF in ARDS and lung cancer.

AUF1-induced circular RNA hsa_circ_0010467 promotes platinum resistance of ovarian cancer through miR-637/LIF/STAT3 axis.

BACKGROUND: Increasing evidences has indicated that primary and acquired resistance of ovarian cancer (OC) to platinum is mediated by multiple molecular and cellular factors. Understanding these mechanisms could promote the therapeutic efficiency for patients with OC. METHODS: Here, we screened the expression pattern of circRNAs in samples derived from platinum-resistant and platinum-sensitive OC patients using RNA-sequencing (RNA-seq). The expression of hsa_circ_0010467 was validated by Sanger sequencing, RT-qPCR, and fluorescence in situ hybridization (FISH) assays. Overexpression and knockdown experiments were performed to explore the function of hsa_circ_0010467. The effects of hsa_circ_0010467 on enhancing platinum treatment were validated in OC cells, mouse model and patient-derived organoid (PDO). RNA pull-down, RNA immunoprecipitation (RIP), and dual-luciferase reporter assays were performed to investigate the interaction between hsa_circ_0010467 and proteins. RESULTS: Increased expression of hsa_circ_0010467 is observed in platinum-resistant OC cells, tissues and serum exosomes, which is positively correlated with advanced tumor stage and poor prognosis of OC patients. Hsa_circ_0010467 is found to maintain the platinum resistance via inducing tumor cell stemness, and silencing hsa_circ_0010467 substantially increases the efficacy of platinum treatment on inhibiting OC cell proliferation. Further investigation reveals that hsa_circ_0010467 acts as a miR-637 sponge to mediate the repressive effect of miR-637 on leukemia inhibitory factor (LIF) and activates the LIF/STAT3 signaling pathway. We further discover that AUF1 could promote the biogenesis of hsa_circ_0010467 in OC. CONCLUSION: Our study uncovers the mechanism that hsa_circ_0010467 mediates the platinum resistance of OC through AUF1/hsa_circ_0010467/miR-637/LIF/STAT3 axis, and provides potential targets for the treatment of platinum-resistant OC patients.

Topology Optimization Driven Bone-Remodeling Simulation for Lumbar Interbody Fusion.

This study proposes a numerical approach for simulating bone remodeling in lumbar interbody fusion (LIF). It employs a topology optimization method to drive the remodeling process and uses a pixel function to describe the structural topology and bone density distribution. Unlike traditional approaches based on strain energy density or compliance, this study adopts von Mises stress to guide the remodeling of LIF. A novel pixel interpolation scheme associated with stress criteria is applied to the physical properties of the bone, directly addressing the stress shielding effect caused by the implanted cage, which significantly influences the bone remodeling outcome in LIF. Additionally, a boundary inverse approach is utilized to reconstruct a simplified analysis model. To reduce computational cost while maintaining high structural resolution and accuracy, the scaled boundary finite element method (SBFEM) is introduced. The proposed numerical approach successfully generates results that closely resemble human lumbar interbody fusion.