Sepsis-associated lung injury arises from a dysregulated response to infection and frequently involves acute respiratory distress syndrome, or ARDS. A meta-analysis cited in the review estimated that ARDS develops in 34.0% of patients with sepsis, with a 95% confidence interval of 29.0% to 39.3%. Lysosomes and related endolysosomal compartments sit directly at the host–pathogen interface: acidic phagolysosomes support microbial killing in macrophages, lamellar bodies participate in surfactant biology in type II alveolar epithelial cells, and lysosomal degradation and trafficking contribute to endothelial repair and fibroblast matrix turnover. Infection-related stress could therefore compromise both pathogen control and the cellular processes needed to preserve the lung’s gas-exchange barrier. The proposed link between these defects and lysosomal pH remains incompletely mapped, however, particularly in human disease.

Central to the hypothesis is the V-ATPase complex, which hydrolyzes ATP to pump protons into lysosomal compartments and create the acidic conditions required by many lysosomal hydrolases. V-ATPase is also a signaling platform influenced by nutrient sensing, trafficking, complex assembly and stress. In macrophages, the ATP6V0D2 subunit has been associated with autophagosome–lysosome fusion and restrained inflammasome activation during bacterial challenge, illustrating that its role cannot be reduced to setting basal acidity. The mTORC1–TFEB pathway provides another connection between nutrient status, lysosomal biogenesis, autophagy and stress adaptation, but the review cautions that TFEB does not uniformly increase every acidification-related transporter across cell types or conditions. Similarly, PI3K–AKT signaling may influence lysosomal resilience indirectly through metabolism, mitochondrial function and membrane stability; a direct AKT-driven alkalinization mechanism has not been established in septic lung cells.

Acidification also depends on the movement of counterions. ClC-7 is a late-endosomal and lysosomal chloride–proton exchanger that requires the accessory protein OSTM1 for stability. Recent work indicates that ClC-7 promotes chloride accumulation in mature phagosomes, hydrolase activity and phagosome resolution. Its influence on bulk lysosomal acidity is more complicated, with genetic studies reporting altered chloride distribution and storage phenotypes without consistent loss of acidification. The authors therefore describe ClC-7 primarily as a regulator of luminal chloride with context-dependent effects on pH. TMEM175, an endolysosomal potassium channel implicated in membrane potential and pH stability, presents another unresolved question. Models disagree over whether it conducts protons or predominantly potassium, and the evidence comes largely from heterologous systems or non-septic neurodegeneration-related models. Its role in pulmonary sepsis has not been directly tested.

A further complication is that lysosomal pH is not equivalent to every other sign of lysosomal dysfunction. The review distinguishes increased luminal pH from membrane permeabilization, reduced hydrolase activity, impaired autophagic flux and changes in lysosomal mass or biogenesis. Markers such as LC3-II, p62, cathepsin abundance and LysoTracker intensity can each be altered by organelle number, trafficking, cargo load, membrane damage or probe behavior. LC3-II accumulation, for example, may reflect either increased autophagy or failure of lysosomal degradation. Direct acidity evidence ideally comes from compartment-targeted ratiometric probes calibrated in situ with ionophores and defined-pH buffers. Single-wavelength acidotropic dyes are useful for locating lysosomes but cannot, by themselves, provide stand-alone pH values. This distinction is especially important in sepsis, where cell death, systemic acid–base disturbances and changes in organelle abundance can confound commonly used readouts.

Microbial and host signals could disturb lysosomal homeostasis in several ways. Lipopolysaccharide activates TLR4–MyD88/TRIF and NF-κB inflammatory signaling in pulmonary immune and structural cells, but available evidence does not show universal repression of acidification machinery. Instead, changes in trafficking, cytokines, nitroxidative stress, metabolism and autophagic flux may indirectly alter lysosomal function. Tumor necrosis factor alpha, interleukin-1 beta and interleukin-6 can promote reactive oxygen species, mitochondrial injury, metabolic reprogramming and dysregulated autophagy–lysosome flux. Persistent stress may reduce ATP-dependent proton pumping, disturb membrane stability or overload degradative capacity. Lysosomal membrane permeabilization can then release cathepsins and other contents into the cytosol. Cathepsin B has been linked to NLRP3 inflammasome activation and pyroptosis-related signaling in experimental sepsis-associated lung injury, but its contribution depends on the cell and stimulus. Reduced lysosomal acidity is thus best considered a possible permissive amplifier working with mitochondrial reactive oxygen species, potassium efflux, danger signals and defective autophagic clearance, not as the sole trigger of inflammation.

The consequences may differ sharply among the cells that form and defend the alveolar–capillary barrier. In macrophages and dendritic cells, impaired lysosomal or phagolysosomal function may reduce microbial killing, cargo degradation and antigen processing, which is why indiscriminate suppression of lysosomal activity could be counterproductive. In epithelial and endothelial cells, lysosomal injury may contribute to protease release, junctional disruption, vascular leakage and defective repair through convergent mechanisms, but direct pH-to-junction causality has not been established. Type II epithelial lamellar bodies have specialized functions in calcium handling and surfactant secretion that should not be equated automatically with canonical lysosomes. During persistent or non-resolving injury, impaired lysosomal degradation may also hinder removal of damaged mitochondria, oxidized lipids and mitochondrial DNA, potentially sustaining TLR9, cGAS–STING and NLRP3 pathways. Evidence linking lysosomal pH to fibrotic matrix remodeling comes mainly from pulmonary fibrosis research, and direct human evidence in post-sepsis lung injury remains limited.

Mitophagy and inter-organelle proton transfer add another possible dimension. Mitochondria and lysosomes communicate through mitophagy, reactive oxygen species, lipid transfer and direct membrane contact sites. Mitochondrial injury can restrict the ATP and redox conditions needed for V-ATPase activity, while defective lysosomal trafficking can reduce mitochondrial clearance and allow dysfunctional mitochondria to accumulate. Studies in yeast and human cells have now shown proton transfer from mitochondria to lysosomes at contact sites, with experimental organelle tethering improving acidification, cargo degradation and autophagic flux. These observations are mechanistically relevant but were not conducted in septic lung models, and no cited sepsis study simultaneously quantified mitochondria–lysosome contacts and lysosomal pH. The relative contributions of V-ATPase and counterion dysfunction, membrane damage and contact-mediated proton transfer therefore remain unresolved in this disease context.

Because the model is not yet ready for clinical application, the authors propose measured rather than diagnostic biomarker panels. A bronchoalveolar lavage fluid strategy could combine calibrated lysosomal pH in recovered alveolar macrophages, intralysosomal cathepsin B and D activity, cytosolic cathepsin redistribution, and extracellular cathepsin or LAMP1/2. A high-pH, low-hydrolase phenotype with limited extracellular release would be consistent with impaired acidification, whereas cathepsin redistribution and extracellular release would favor membrane injury. A less invasive blood panel could assess calibrated pH in circulating monocytes, cathepsin localization and autophagic flux, although neither LC3-II nor p62 alone would establish alkalinization. These are proposed test strategies rather than validated signatures and would require longitudinal cohorts, comparison with established measures such as oxygenation, lactate, procalcitonin and inflammatory markers, and analysis of whether blood and lung samples identify the same phenotypes.

Therapeutic development would likewise need to distinguish disease phase and molecular phenotype. An alkalinization-dominant state with impaired phagocyte degradation could justify testing controlled restoration of acidification or lysosomal biogenesis. One compound, ZLN005, increased lysosomal acidity and biogenesis in phagocytes and improved bacterial killing and survival in experimental polymicrobial sepsis, but its effects also involved PGC-1α, PI3K and TFEB, preventing attribution of benefit solely to pH correction. Selectively applicable clinical V-ATPase activators are not established. Conversely, a membrane-injury phenotype without clear alkalinization would support testing membrane stabilization or carefully titrated protease modulation, since broad cathepsin inhibition could interfere with microbial killing and tissue remodeling. Future experiments should combine spatial or single-cell identification of lysosomal stress with calibrated pH measurement, hydrolase assays, membrane-permeabilization tests and flux analysis in infection models, co-cultures, organoids and precision-cut lung slices. The defensible conclusion is that lysosomal pH homeostasis deserves testing as a mechanistic and stratification axis for sepsis-associated lung injury, not that it has already been established as a precision-medicine target.

Subject of Research: Lysosomal pH dysregulation as a candidate amplifier of sepsis-associated lung injury

Article Title: Lysosomal pH dysregulation as a candidate signal-amplifying hub in sepsis-associated lung injury

Article References: Tu, G., Deng, Z., Li, Y., Tian, P., Shen, Y., Deng, Y., Zhang, Z., Liu, Y., Zhong, S., Wu, J., Zhu, H., Ma, J., & Li, J. (2026). Lysosomal pH dysregulation as a candidate signal-amplifying hub in sepsis-associated lung injury. Frontiers in Cellular and Infection Microbiology, 16, Article 1953667. https://doi.org/10.3389/fcimb.2026.1953667

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1953667

Keywords: lysosomal pH, sepsis, lung injury, ARDS, V-ATPase, inflammation, autophagy, mitochondria–lysosome crosstalk, host–pathogen interaction, Lysosomal, dysregulation, candidate