pH Homeostasis Research Articles

Design, synthesis, and biological activity studies of carbonic anhydrase inhibitors.

Carbonic anhydrase (CA) enzymes are a common catalytic enzyme in many organisms. Vertebrates and invertebrates have different CA isoforms. Sixteen different isozymes of the α-CA isoform found in vertebrates have been identified so far. The main task of this enzyme is to catalyze the reversible conversion of carbon dioxide into bicarbonate and hydrogen ions in the body. It is widely distributed in many organs and tissues. They are involved in important physiological processes such as pH and CO2 homeostasis, biosynthetic reactions such as gluconeogenesis, lipogenesis, ureagenesis, bone resorption, calcification, tumorigenicity, and electrolyte secretion. As a result of the literature research, it has been determined that the most effective inhibitor of the carbonic anhydrase enzyme is sulfonamides. The R group in the general molecular structure of R-SO2-NH2 generally consists of aromatic or heteroaromatic ring systems. The sulfonamides interact strongly with the Zn2+ ions in the active site of the enzyme. In this study, 10 sulfonamide derivatives were synthesized. Analyses of the obtained compounds are evaluated by using 1H NMR, 13C NMR and HRMS spectroscopic methods. The inhibition effect of the obtained compounds on the carbonic anhydrase enzyme was investigated by means of invitro kit method. For the selected compounds, docking studies were performed and the enzyme active sites and binding points were determined. It was revealed that the strongest interaction with CA enzymes (CA-I, CA-II, CA-IX, CA-XII) active sites was observed with the compound 2e.

Unveiling the molecular basis of Stem-Physical-Strength-Mediated-Resistance (SPSMR) mechanism against Sclerotinia sclerotiorum in oilseed Brassica: A comparative transcriptome analysis between resistant Sinapis alba and susceptible Brassica juncea

This study elucidates the intricate molecular dynamics of the Stem-Physical-Strength-Mediated-Resistance (SPSMR) mechanism against Sclerotinia sclerotiorum in oilseed Brassica. This study explores how resistant and susceptible genotypes respond to S. sclerotiorum and their stem physical strength at various infection stages, revealing the molecular basis of SPSMR-mechanism. Statistically significant differences (P ≤ 0.05) were observed between genotypes over time, where the resistant genotype showed reduced stem lesion length, stem diameter, and stem water content, along with increased stem dry matter content, stem specific density, stem breaking force, stem breaking strength, and lignin content compared to the susceptible counterpart. Through gene expression analysis, the study unraveled unique patterns of differentially expressed genes linked to cell wall reinforcement, pathogenesis and disease resistance. Upregulation of genes associated with arabinogalactan protein, xyloglucan endotransglucosylase/hydrolase, pectinesterase, expansins, S-adenosylmethionine-dependent methyltransferase, wall-associated kinases, peroxidases, laccases and phenylalanine ammonia-lyase as well as other genes associated with lignin-biosynthesis was evident in the resistant genotype. Additionally, gene ontology and KEGG enrichment analyses highlights the synergy between stem physical strength and molecular components, revealing a distinctive defense strategy involving the coordinated upregulation of genes responsible for cell-wall strengthening, disease resistance, and pathogenesis-related proteins in the resistant genotype. Conversely, compromised expression patterns in the susceptible genotype underscore its challenge in mounting a robust defense. Strikingly, genes regulating intracellular pH homeostasis emerge as potential countermeasures against S. sclerotiorum virulence. Ultimately, these findings provide a new perspective on the molecular basis of the SPSMR mechanism in boosting host genetic resistance against S. sclerotiorum in oilseed Brassica and other hosts. However, future research is required to investigate diverse genotypes, additional pathways, and regulatory elements in order to achieve a comprehensive understanding of SPSMR in oilseed Brassica.

The conserved evolution of plant H+-ATPase family and the involvement of soybean H+-ATPases in sodium bicarbonate stress responses

Plant plasma membrane (PM) H+-ATPases are essential pumps involved in multiple physiological processes. They play a significant role in regulating pH homeostasis and membrane potential by generating the electrochemical gradient of the proton across the plasma membrane. However, information on soybean PM H+-ATPase is still limited. In this study, we conducted the evolutionary analysis of PM H+-ATPases in land plants and investigated the subfamily classification and whole genome duplication of PM H+-ATPases in angiosperms. We further characterized the extremely high conservation of the soybean PM H+-ATPase family in terms of gene structure, domain architecture, and protein sequence identity. Using the yeast system, we confirmed the highly conserved biochemical characteristics (14-3-3 binding affinity and pump activity) of soybean PM H+-ATPases and their conserved function in enhancing tolerance to high pH and NaHCO3 stresses. Meanwhile, our results also revealed their divergence in the transcriptional expression in different tissues and under sodium bicarbonate stress. Finally, the function of soybean PM H+-ATPases in conferring sodium bicarbonate tolerance was validated using transgenic Arabidopsis. Together, these results conclude that the soybean PM H+-ATPase is evolutionarily conserved and positively regulates the response to sodium bicarbonate stress.

RhoA balances microglial reactivity and survival during neuroinflammation

Microglia are the largest myeloid cell population in the brain. During injury, disease, or inflammation, microglia adopt different functional states primarily involved in restoring brain homeostasis. However, sustained or exacerbated microglia inflammatory reactivity can lead to brain damage. Dynamic cytoskeleton reorganization correlates with alterations of microglial reactivity driven by external cues, and proteins controlling cytoskeletal reorganization, such as the Rho GTPase RhoA, are well positioned to refine or adjust the functional state of the microglia during injury, disease, or inflammation. Here, we use multi-biosensor-based live-cell imaging approaches and tissue-specific conditional gene ablation in mice to understand the role of RhoA in microglial response to inflammation. We found that a decrease in RhoA activity is an absolute requirement for microglial metabolic reprogramming and reactivity to inflammation. However, without RhoA, inflammation disrupts Ca2+ and pH homeostasis, dampening mitochondrial function, worsening microglial necrosis, and triggering microglial apoptosis. Our results suggest that a minimum level of RhoA activity is obligatory to concatenate microglia inflammatory reactivity and survival during neuroinflammation.

Identification and characterization of salt stress-responsive NHX gene family in chickpea

Chickpea (Cicer arietinum L.) is an important legume crop, primarily grown in the arid and semi-arid regions. It is a valuable protein source and rich in minerals, especially calcium and phosphorus. Salinity stress adversely affects chickpea germination, vegetative growth, and reproductive activities. The Na+/H+ exchanger (NHX), a gene family of membrane transporters, is well recognized for inducing salt tolerance in plants. The NHXs assist in maintaining ion and pH homeostasis in cells by exchanging K+ or Na+ for H+. This study was designed to identify and characterize the NHX genes for salt stress responsiveness in chickpea. Eight NHX genes were identified in chickpea. The phylogenetic analysis represented the evolutionary relationship of Cicer arietinum NHXs (CarNHXs) with Glycine max, Medicago truncatula, Lotus japonicus, Phaseolus vulgaris, Lens culinaris, Vigna unguiculata, and Oryza sativa. The in-silico gene expression analysis indicated high expression of CarNHX3 (Ca_19073) and CarNHX7 (Ca_02050) under salt stress. The qRT-PCR further validated that the expression of CarNHX3 and CarNHX7 increased when plants were exposed to salt stress. This study provides a way forward to plan functional research to exploit CarNHX genes to enhance salt-tolerance in chickpea.

How do plants maintain pH and ion homeostasis under saline-alkali stress?

Salt and alkaline stresses often occur together, severely threatening plant growth and crop yields. Salt stress induces osmotic stress, ionic stress, and secondary stresses, such as oxidative stress. Plants under saline-alkali stress must develop suitable mechanisms for adapting to the combined stress. Sustained plant growth requires maintenance of ion and pH homeostasis. In this review, we focus on the mechanisms of ion and pH homeostasis in plant cells under saline-alkali stress, including regulation of ion sensing, ion uptake, ion exclusion, ion sequestration, and ion redistribution among organs by long-distance transport. We also discuss outstanding questions in this field.

The hybrid RAVE complex plays V-ATPase-dependent and -independent pathobiological roles in Cryptococcus neoformans.

V-ATPase, which comprises 13-14 subunits, is essential for pH homeostasis in all eukaryotes, but its proper function requires a regulator to assemble its subunits. While RAVE (regulator of H+-ATPase of vacuolar and endosomal membranes) and Raboconnectin-3 complexes assemble V-ATPase subunits in Saccharomyces cerevisiae and humans, respectively, the function of the RAVE complex in fungal pathogens remains largely unknown. In this study, we identified two RAVE complex components, Rav1 and Wdr1, in the fungal meningitis pathogen Cryptococcus neoformans, and analyzed their roles. Rav1 and Wdr1 are orthologous to yeast RAVE and human Rabconnectin-3 counterparts, respectively, forming the hybrid RAVE (hRAVE) complex. Deletion of RAV1 caused severe defects in growth, cell cycle control, morphogenesis, sexual development, stress responses, and virulence factor production, while the deletion of WDR1 resulted in similar but modest changes, suggesting that Rav1 and Wdr1 play central and accessary roles, respectively. Proteomics analysis confirmed that Wdr1 was one of the Rav1-interacting proteins. Although the hRAVE complex generally has V-ATPase-dependent functions, it also has some V-ATPase-independent roles, suggesting a unique role beyond conventional intracellular pH regulation in C. neoformans. The hRAVE complex played a critical role in the pathogenicity of C. neoformans, and RAV1 deletion attenuated virulence and impaired blood-brain barrier crossing ability. This study provides comprehensive insights into the pathobiological roles of the fungal RAVE complex and suggests a novel therapeutic strategy for controlling cryptococcosis.

Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this pH landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) to induce PDAC fibrosis. We revealed that alkaline environmental pH was sufficient to induce PSC differentiation to a myofibroblastic phenotype. We then mechanistically dissected this finding, focusing on the involvement of the Na+/H+ exchanger NHE1. Perturbing cellular pH homeostasis by inhibiting NHE1 with cariporide partially altered the myofibroblastic PSC phenotype. To show the relevance of this finding in vivo, we targeted NHE1 in murine PDAC (KPfC). Indeed, tumor fibrosis decreased when mice received the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifted from granulocyte rich to more lymphocytic. Taken together, our study provides mechanistic evidence on how the pancreatic pH landscape shapes pancreatic cancer through tuning PSC differentiation.

Modification of the second PEP4-allele facilitates an industrial Saccharomyces cerevisiae to tolerate tartaric acid stress

The practical significance of constructing robust industrial production strains against organic acid stress lies not only in improving fermentation efficiency but also in reducing manufacturing costs. In a previous study, we constructed an industrial Saccharomyces cerevisiae strain by modifying another PEP4-allele of a mutant that already had one PEP4-allele disrupted. This modification enhanced cellular tolerance to citric acid stress during growth. Unlike citric acid, which S. cerevisiae can consume, tartaric acid is often added to grape must during winemaking to increase total acidity and is not metabolizable. The results of the present study indicate that the modification of the second PEP4-allele improves the cellular tolerance of the strain with one PEP4-allele disrupted against tartaric acid stress during growth and contributes to maintaining intracellular pH homeostasis in cells subjected to tartaric acid stress. Moreover, under tartaric acid stress, a significant improvement in glucose-ethanol conversion performance, conferred by the modification of the second PEP4-allele, was observed. This study not only broadens our understanding of the role of the PEP4-allele in cellular regulation but also provides a prospective approach to reducing the concentration of sulfur dioxide used in winemaking.

Estrogen-Induced LncRNA, LINC02568, Promotes Estrogen Receptor-Positive Breast Cancer Development and Drug Resistance Through Both In Trans and In Cis Mechanisms.

Endocrine therapy is the frontline treatment for estrogen receptor (ER) positive breast cancer patients. However, the primary and acquired resistance to endocrine therapy drugs remain as a major challenge in the clinic. Here, this work identifies an estrogen-induced lncRNA, LINC02568, which is highly expressed in ER-positive breast cancer and functional important in cell growth in vitro and tumorigenesis in vivo as well as endocrine therapy drug resistance. Mechanically, this work demonstrates that LINC02568 regulates estrogen/ERα-induced gene transcriptional activation in trans by stabilizing ESR1 mRNA through sponging miR-1233-5p in the cytoplasm. Meanwhile, LINC02568 contributes to tumor-specific pH homeostasis by regulating carbonic anhydrase CA12 in cis in the nucleus. The dual functions of LINC02568 together contribute to breast cancer cell growth and tumorigenesis as well as endocrine therapy drug resistance. Antisense oligonucleotides (ASO) targeting LINC02568 significantly inhibits ER-positive breast cancer cell growth in vitro and tumorigenesis in vivo. Furthermore, combination treatment with ASO targeting LINC02568 and endocrine therapy drugs or CA12 inhibitor U-104 exhibits synergistic effects on tumor growth. Taken together, the findings reveal the dual mechanisms of LINC02568 in regulating ERα signaling and pH homeostasis in ER-positive breast cancer, and indicated that targeting LINC02568 might represent a potential therapeutic avenue in the clinic.

Alkalinity modulates a unique suite of genes to recalibrate growth and pH homeostasis.

Alkaline soils pose a conglomerate of constraints to plants, restricting the growth and fitness of non-adapted species in habitats with low active proton concentrations. To thrive under such conditions, plants have to compensate for a potential increase in cytosolic pH and restricted softening of the cell wall to invigorate cell elongation in a proton-depleted environment. To discern mechanisms that aid in the adaptation to external pH, we grew plants on media with pH values ranging from 5.5 to 8.5. Growth was severely restricted above pH 6.5 and associated with decreasing chlorophyll levels at alkaline pH. Bicarbonate treatment worsened plant performance, suggesting effects that differ from those exerted by pH as such. Transcriptional profiling of roots subjected to short-term transfer from optimal (pH 5.5) to alkaline (pH 7.5) media unveiled a large set of differentially expressed genes that were partially congruent with genes affected by low pH, bicarbonate, and nitrate, but showed only a very small overlap with genes responsive to the availability of iron. Further analysis of selected genes disclosed pronounced responsiveness of their expression over a wide range of external pH values. Alkalinity altered the expression of various proton/anion co-transporters, possibly to recalibrate cellular proton homeostasis. Co-expression analysis of pH-responsive genes identified a module of genes encoding proteins with putative functions in the regulation of root growth, which appears to be conserved in plants subjected to low pH or bicarbonate. Our analysis provides an inventory of pH-sensitive genes and allows comprehensive insights into processes that are orchestrated by external pH.

A study to assess the effectiveness of Self-instructional Module on knowledge regarding ABG among student nurses in selected college of city

Arterial blood gas analysis is a basic and useful laboratory test for the critical care of patient. ABG is an essential investigation for assessing clinical oxygenation and acid base status in critically ill patient, providing information about ventilation, oxygenation and acid base status, the three closely and interrelated physiological parameters that maintain pH homeostasis. Among student Nurses in selected college of city. An arterial blood Gas (ABG) tests explicitly blood taken from an artery ABG analysis assesses a patient’s partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2). The objectives of study were to assess existing level of knowledge regarding ABG analysis among the students nurses in selected college, Assess the post test knowledge regarding the ABG analysis among the student nurses in selected college, to assess the effectiveness of SIM on ABG analysis among the students nurses in Selected college, to find out the association between post-test levels of knowledge with selected Demographic level. A structured questionnaire to collect the knowledge score was use for data collection and the analysis was done with the help of inferential and descriptive statistics. The data collection was done from 60 samples from basic BSc nursing 3rd year students. The pre test shows 26.67% of the nursing student had poor level of knowledge score, 58.33% had average and 15% had good level of knowledge score. The post test shows 5% nursing student had average level of knowledge score 35% had good and 60% of nursing student have excellent level of knowledge score. The calculated t value is 15.07 are much higher than the tabulated value at 5% level of significance. Hence it is statistically interpreted that the self-instructional module on knowledge regarding ABG analysis among nursing students was effective

Brain transcriptome of gobies inhabiting natural CO2 seeps reveal acclimation strategies to long-term acidification.

Ocean acidification (OA) is known to affect the physiology, survival, behaviour and fitness of various fish species with repercussions at the population, community and ecosystem levels. Some fish species, however, seem to acclimate rapidly to OA conditions and even thrive in acidified environments. The molecular mechanisms that enable species to successfully inhabit high CO2 environments have not been fully elucidated especially in wild fish populations. Here, we used the natural CO2 seep in Vulcano Island, Italy to study the effects of elevated CO2 exposure on the brain transcriptome of the anemone goby, a species with high population density in the CO2 seep and investigate their potential for acclimation. Compared to fish from environments with ambient CO2, gobies living in the CO2 seep showed differences in the expression of transcripts involved in ion transport and pH homeostasis, cellular stress, immune response, circadian rhythm and metabolism. We also found evidence of potential adaptive mechanisms to restore the functioning of GABAergic pathways, whose activity can be affected by exposure to elevated CO2 levels. Our findings indicate that gobies living in the CO2 seep may be capable of mitigating CO2-induced oxidative stress and maintaining physiological pH while meeting the consequent increased energetic costs. The conspicuous difference in the expression of core circadian rhythm transcripts could provide an adaptive advantage by increasing the flexibility of physiological processes in elevated CO2 conditions thereby facilitating acclimation. Our results show potential molecular processes of acclimation to elevated CO2 in gobies enabling them to thrive in the acidified waters of Vulcano Island.

Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel

Maintaining a highly acidic lysosomal pH is central to cellular physiology. Here, we use functional proteomics, single-particle cryo-EM, electrophysiology, and invivo imaging to unravel a key biological function of human lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in regulating lysosomal pH homeostasis. Despite being widely used as a lysosomal marker, the physiological functions of the LAMP proteins have long been overlooked. We show that LAMP-1 and LAMP-2 directly interact with and inhibit the activity of the lysosomal cation channel TMEM175, a key player in lysosomal pH homeostasis implicated in Parkinson's disease. This LAMP inhibition mitigates the proton conduction of TMEM175 and facilitates lysosomal acidification to a lower pH environment crucial for optimal hydrolase activity. Disrupting the LAMP-TMEM175 interaction alkalinizes the lysosomal pH and compromises the lysosomal hydrolytic function. In light of the ever-increasing importance of lysosomes to cellular physiology and diseases, our data have widespread implications for lysosomal biology.

Arabidopsis mutants lacking DLDG1 and non-photochemical quenching-related proteins reveal the regulatory role of DLDG1 in chloroplast pH homeostasis.

The control of pH in chloroplasts is important to regulate photosynthesis, although details of the precise regulatory mechanisms of H+ homeostasis in chloroplasts are not fully understood. We recently found that the cyanobacterial PxcA homolog DLDG1 is involved in plastidial pH control. PxcA and DLDG1 have been thought to control light-dependent H+ extrusion across the cyanobacterial cytoplasmic and chloroplast envelope membranes, respectively. To investigate DLDG1-dependent pH control in chloroplasts, we crossed the dldg1 mutant with various mutants lacking known non-photochemical quenching (NPQ)-related proteins, such as fluctuating-light acclimation protein 1 (FLAP1), PsbS/NPQ4, and proton gradient regulation 5 (PGR5). Phenotypes of these double mutants revealed that PsbS works upstream of DLDG1, PGR5 affects NPQ independently from DLDG1, and the ΔpH regulation by FLAP1 and DLDG1 are independent of each other.

Voltage-Gated Proton Channels in the Tree of Life.

With a single gene encoding HV1 channel, proton channel diversity is particularly low in mammals compared to other members of the superfamily of voltage-gated ion channels. Nonetheless, mammalian HV1 channels are expressed in many different tissues and cell types where they exert various functions. In the first part of this review, we regard novel aspects of the functional expression of HV1 channels in mammals by differentially comparing their involvement in (1) close conjunction with the NADPH oxidase complex responsible for the respiratory burst of phagocytes, and (2) in respiratory burst independent functions such as pH homeostasis or acid extrusion. In the second part, we dissect expression of HV channels within the eukaryotic tree of life, revealing the immense diversity of the channel in other phylae, such as mollusks or dinoflagellates, where several genes encoding HV channels can be found within a single species. In the last part, a comprehensive overview of the biophysical properties of a set of twenty different HV channels characterized electrophysiologically, from Mammalia to unicellular protists, is given.

Atorvastatin Exerts More Selective Inhibitory Effects on hMCT2 than on hMCT1 and hMCT4.

Human monocarboxylate transporter 1 (hMCT1), hMCT2, and hMCT4 transport monocarboxylates, such as L-lactate and pyruvate, with pH dependency. They are often over-expressed in various cancer cells and mediate the energy balance and pH homeostasis. Therefore, hMCT inhibitors can potentially be used as anticancer drugs. However, isoform-selective inhibitors have not yet been well-characterized. In addition, several statins and 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors have been reported to inhibit hMCTs, but their selectivity has not yet been evaluated. In this study, we aimed to determine whether statins could inhibit hMCT1, hMCT2, and hMCT4. We expressed hMCT1, hMCT2, and hMCT4 in a heterologous expression system of Xenopus oocytes and performed inhibitory experiments with various statins (fluvastatin, atorvastatin, simvastatin, rosuvastatin, pravastatin, and pitavastatin). As the three-dimensional structure of hMCT2 has been recently reported, docking simulations of statins and their structures were also performed to estimate the inhibition site. All statins inhibited the transport activities of hMCT1, hMCT2, and hMCT4. In addition, atorvastatin was found to be a potent isoform-selective inhibitor of hMCT2. Docking simulation indicated that atorvastatin could interact with a site surrounded by transmembrane (TM)-2, TM11, and intracellular helix in the TM6/7loop. Therefore, targeting this site may lead to the discovery of more potent hMCT2-selective inhibitors. Atorvastatin exerts selective inhibitory effects on hMCT2. These findings provide insights into the inhibitory mechanism of statins against hMCT1, hMCT2, and hMCT4 and may aid in the development of novel anticancer agents.

Structural and functional properties of the transporter SLC26A6 reveal mechanism of coupled anion exchange

Members of the SLC26 family constitute a conserved class of anion transport proteins, which encompasses uncoupled transporters with channel-like properties, coupled exchangers and motor proteins. Among the 10 functional paralogs in humans, several participate in the secretion of bicarbonate in exchange with chloride and thus play an important role in maintaining pH homeostasis. Previously, we have elucidated the structure of murine SLC26A9 and defined its function as an uncoupled chloride transporter (Walter et al., 2019). Here we have determined the structure of the closely related human transporter SLC26A6 and characterized it as a coupled exchanger of chloride with bicarbonate and presumably also oxalate. The structure defines an inward-facing conformation of the protein that generally resembles known structures of SLC26A9. The altered anion selectivity between both paralogs is a consequence of a remodeled ion binding site located in the center of a mobile unit of the membrane-inserted domain, which also accounts for differences in the coupling mechanism.

Structural and functional properties of the transporter SLC26A6 reveal mechanism of coupled anion exchange.

Members of the SLC26 family constitute a conserved class of anion transport proteins, which encompasses uncoupled transporters with channel-like properties, coupled exchangers and motor proteins. Among the 10 functional paralogs in humans, several participate in the secretion of bicarbonate in exchange with chloride and thus play an important role in maintaining pH homeostasis. Previously, we have elucidated the structure of murine SLC26A9 and defined its function as an uncoupled chloride transporter (Walter et al., 2019). Here we have determined the structure of the closely related human transporter SLC26A6 and characterized it as a coupled exchanger of chloride with bicarbonate and presumably also oxalate. The structure defines an inward-facing conformation of the protein that generally resembles known structures of SLC26A9. The altered anion selectivity between both paralogs is a consequence of a remodeled ion binding site located in the center of a mobile unit of the membrane-inserted domain, which also accounts for differences in the coupling mechanism.

Near-infrared-activated anticancer platinum(IV) complexes directly photooxidize biomolecules in an oxygen-independent manner.

Conventional light-driven cancer therapeutics require oxygen and visible light to indirectly damage biomolecules, limiting their efficacy in deep, hypoxic tumours. Here we report the use of near-infrared-activated small-molecule Pt(IV) photooxidants to directly oxidize intracellular biomolecules in an oxygen-independent manner, achieving controllable and effective elimination of cancer stem cells. These Pt(IV) complexes accumulate in the endoplasmic reticulum and show low toxicity in the dark. Upon irradiation, the resultant metal-enhanced photooxidation effect causes them to robustly photooxidize survival-related biomolecules, induce intense oxidative stress, disrupt intracellular pH (pHi) homeostasis and initiate nonclassical necrosis. In vivo experiments confirm that the lead photooxidant can effectively inhibit tumour growth, suppress metastasis and activate the immune system. Our study validates the concept of metal-enhanced photooxidation and the subsequent chemotherapeutic applications, supporting the development of such localized photooxidants to directly damage intracellular biomolecules and decrease pHi as a strategy for effective metal-based drugs.