The increased prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide is particularly worrisome, as no medication has been approved to treat the disease. Lifestyle modifications aimed at promoting weight loss and weight maintenance remain the current first-line treatment for NAFLD. However, due to the lack of standard and scientific guidance and out-of-hospital supervision, long-term outcomes of lifestyle interventions for patients with NAFLD are often unsatisfactory. In addition, the COVID-19 pandemic aggravated this dilemma. At the same time, digital therapeutics (DTx) are expected to be a new method for the convenient management and treatment of patients with NAFLD and are attracting a great deal of attention. DTx, which provide evidence-based medicine through software programs for remote intervention in preventing, treating, or managing diseases, overcome the drawbacks of traditional treatment. The efficacy of the approach has already been demonstrated for some chronic diseases, but DTx have not been fully developed for NAFLD. This study reviews the concepts, clinical value, and practical applications related to DTx, with an emphasis on recommendations based on unmet needs for NAFLD. A better understanding of the current state will help clinicians and researchers develop high-quality, standardized, and efficient DTx products, with the aim of optimizing the prognosis of patients with NAFLD.

Background: Hepatic Ischemia-Reperfusion Injury (IRI) is a critical complication in liver transplantation and resection, driven by oxidative stress and sterile inflammation mediated by damage-associated molecular patterns (DAMPs). Current therapeutic challenges arise from interconnected cell death pathways and redundant inflammatory mechanisms. Objective: This review synthesizes mechanistic insights into DAMP signaling and regulated cell death modalities in IRI, aiming to identify translational gaps and propose precision-targeted therapies. Methods: A literature search in PubMed using keywords “IRI,” “DAMPs,” and cell death modes was conducted without date restrictions. Peer-reviewed studies on human/animal models were included, with qualitative synthesis of DAMP-cell death interactions. Results: During ischemia, mitochondrial dysfunction releases HMGB1, ATP, and mtDNA, activating Kupffer cell TLR4/RAGE and cGAS-STING pathways, triggering NLRP3 inflammasomedriven cytokine storms. Reperfusion amplifies ROS bursts, lipid peroxidation, and iron overload, creating a self-sustaining cycle of damage. Cell death modalities exhibit spatiotemporal specificity: hepatocyte ferroptosis dominates early injury, while macrophage pyroptosis and necroptosis predominate in steatotic livers during late phases. HMGB1 lactylation and mtDNA-cGAS signaling emerge as key regulators. Machine perfusion (e.g., hypothermic oxygenated perfusion) reduces biliary complications via mitochondrial resuscitation, outperforming conventional drugbased therapies. Conclusion: Current single-pathway targeting shows limited efficacy due to IRI’s complexity. Future strategies should integrate temporal targeting (ferroptosis inhibitors pre-reperfusion; pyroptosis blockers post-reperfusion), DAMP-neutralizing agents (anti-HMGB1 antibodies), and precision preservation combining multi-omics biomarkers with ex vivo pharmacological preconditioning. Addressing metabolic vulnerabilities in fatty livers and refining cell death-specific interventions are critical for bridging translational gaps.

Purpose: The biomechanical capacity of “Barrel Hoop Plate (BHP)” in the treatment of the posterolateral tibial plateau (PL) depression fractures remains unknown. In this study, two kinds of posterolateral tibial plateau depression models involving mild slope-type depression fracture (MSDF) and local sink hole-type depression fracture (LSDF) were created to test and compare the biomechanical capacities of BHP with the other two conventional fixations (Anterolateral Plate and Posterolateral Plate, ALP and PLP) by finite element analysis. Methods: The 3D models of three kinds of plate-screw systems and the two kinds of PL-depression models (MSDF and LSDF) were created. An axial force of 400N was applied from the distal femur to the tibial plateau. The maximal displacements of the posterolateral fractures (PLFs), the distribution on the PLFs articular surface and key points displacements were measured. Stresses in the fixation complex including the maximal Equivalent (von-Mises) Stress of implants, the max shear stress of PLFs and stiffness of the fixation were calculated. Results: The maximal displacement of MSDF was least in Group BHP. The maximal displacement of LSDF was least in Group ALP. In MSDF, BHP showed the best rim fix effect in MSDF, but unsatisfactory results in LSDF. In both MSDF and LSDF, the greatest max Equivalent Stress of the plate and the screw occurred in the PLP system. ALP and BHP showed a comparable stiffness in MSDF and ALP had the strongest stiffness in the fixation of LSDF. Conclusions: In MSDF, the BHP has the best biomechanical capacity, especially in displacements of key points such as the PL rim, fracture line, and depression center. In LSDF, the ALP system shows the best biomechanical effect. Although the PLP has the best fixation effect on the posterior wall, it is not suitable for PL-depression fracture fixation.

Natural Killer (NK) cells serve a critical function in antitumor immunity. However, their effectiveness is often hampered by the biomechanical properties of the solid tumor microenvironment (TME), such as the stiffness of the extracellular matrix. This review focuses on the mechanosensitive ion channel Piezo1 and its role in enhancing NK cell function. Studies have shown that tumor cell stiffness, as a key physical cue, directly influences the responsiveness of NK cells. In three-dimensional (3D) matrices, the stiffening of the extracellular matrix (ECM) can activate Piezo1, leading to calcium influx that substantially boosts NK cells’ cytotoxicity and tumor infiltration ability. Remarkably, similar to Yoda1, a specific Piezo1 agonist, short-term Piezo1 activation significantly enhances NK cells’ cytotoxicity and infiltration capacity. Whether such benefits persist under prolonged stimulation without inducing functional exhaustion remains to be determined. Unlike broader review articles that discuss TME biomechanics, this study focuses on uncovering the signal transduction mechanism of the Piezo1–NK cell axis, providing new perspectives and strategies for addressing immunotherapy resistance. This mechanobiology-based framework, through detailed analysis of the Piezo1-NK cell signaling transduction mechanism, is expected to overcome bottlenecks in NK cell immunotherapy. Its application prospects are not limited to the field of oncology but can also be extended to other diseases sensitive to mechanical signals.

Rheumatoid arthritis (RA) is sustained not only by immune activation within the synovium but also by dysfunction of the lymphatic network that normally clears interstitial fluid, inflammatory mediators, and leukocytes migrating from inflamed tissues. Functional abnormalities in lymph node stromal cells may arise before clinically apparent arthritis. After RA becomes established, the lymphatic response may shift from compensatory lymphangiogenesis to reduced collecting-vessel contraction, structural deterioration of draining lymph nodes, and impaired lymphatic drainage. This review examines how IL-33/ST2 signaling, neutrophil extracellular traps (NETs), and the lymphatic endothelial program maintained by PROX1 may influence the shift from compensatory remodeling to lymphatic dysfunction. During early inflammation, IL-33 can activate the ST2/TRAF6/PI3K/Akt/eNOS/NO pathway in lymphatic endothelial cells (LECs), while VEGF-C/VEGFR3 signaling supports lymphatic vessel growth and fluid transport. But vessel expansion does not guarantee that newly formed lymphatics mature or restore effective drainage. As inflammation persists, TNF-driven iNOS activity, occupation of lymphatic sinuses by B cells, and structural changes in draining lymph nodes can reduce lymphatic transport and prolong synovial exposure to cytokines, immune complexes, and autoantigens. NETs directly injure lymphatic endothelium in inflammatory models outside RA, but direct evidence in synovial LECs remains unavailable. NET-associated histones, proteases, myeloperoxidase, extracellular DNA, and HMGB1 should therefore be considered plausible rather than established mediators of LEC injury through junctional disruption, oxidative stress, or RAGE- and TLR9-related signaling. Reduced PROX1 activity may further weaken lymphatic endothelial identity by disrupting the expression of VEGFR3, LYVE1, PDPN, and CCL21, which support vessel maintenance and immune-cell transport. Based on these findings, we propose a stage-dependent model in which established IL-33–NET–fibroblast-like synoviocyte and IL-33–macrophage circuits increase the inflammatory burden, while declining lymphatic clearance retains the mediators that sustain these circuits. This framework separates demonstrated mechanisms from untested links and identifies synovial LEC injury, lymphatic transport, and stage-specific pathway modulation as priorities for mechanistic studies and therapeutic development.