Soluble Methane Monooxygenase.

Aerobic life is possible because the molecular structure of oxygen (O2) makes direct reaction with most organic materials at ambient temperatures an exceptionally slow process. Of course, these reactions are inherently very favorable, and they occur rapidly with the release of a great deal of energy at high temperature. Nature has been able to tap this sequestered reservoir of energy with great spatial and temporal selectivity at ambient temperatures through the evolution of oxidase and oxygenase enzymes. One mechanism used by these enzymes for O2 activation has been studied in detail for the soluble form of the enzyme methane monooxygenase. These studies have revealed the step-by-step process of O2 activation and insertion into the ultimately stable C-H bond of methane. Additionally, an elegant regulatory mechanism has been defined that enlists size selection and quantum tunneling to allow methane oxidation to occur specifically in the presence of more easily oxidized substrates.

The Ribofilm as a Concept for Life's Origins.

Recent phylogenetic data indicating that the first archaea were methane-producing galvanizes cross-disciplinary evidence supporting the hypothesis that life arose via thermodynamically directed events at hydrothermal vents. The new developments lead us to propose the concept of a ribofilm in which RNA's origin-of-life role is more akin to a slowly changing platform than a spontaneous self-replicator.

Unlocking carbene reactivity by metallaphotoredox α-elimination.

The ability to tame high-energy intermediates is important for synthetic chemistry, enabling the construction of complex molecules and propelling advances in the field of synthesis. Along these lines, carbenes and carbenoid intermediates are particularly attractive, but often unknown, high-energy intermediates1,2. Classical methods to access metal carbene intermediates exploit two-electron chemistry to form the carbon-metal bond. However, these methods are usually prohibitive because of reagent safety concerns, limiting their broad implementation in synthesis3-6. Mechanistically, an alternative approach to carbene intermediates that could circumvent these pitfalls would involve two single-electron steps: radical addition to metal to forge the initial carbon-metal bond followed by redox-promoted α-elimination to yield the desired metal carbene intermediate. Here we realize this strategy through a metallaphotoredox platform that exploits iron carbene reactivity using readily available chemical feedstocks as radical sources and α-elimination from six classes of previously underexploited leaving groups. These discoveries permit cyclopropanation and σ-bond insertion into N-H, S-H and P-H bonds from abundant and bench-stable carboxylic acids, amino acids and alcohols, thereby providing a general solution to the challenge of carbene-mediated chemical diversification.

Country-specific net-zero strategies of the pulp and paper industry.

The pulp and paper industry is an important contributor to global greenhouse gas emissions1,2. Country-specific strategies are essential for the industry to achieve net-zero emissions by 2050, given its vast heterogeneities across countries3,4. Here we develop a comprehensive bottom-up assessment of net greenhouse gas emissions of the domestic paper-related sectors for 30 major countries from 1961 to 2019-about 3.2% of global anthropogenic greenhouse gas emissions from the same period5-and explore mitigation strategies through 2,160 scenarios covering key factors. Our results show substantial differences across countries in terms of historical emissions evolution trends and structure. All countries can achieve net-zero emissions for their pulp and paper industry by 2050, with a single measure for most developed countries and several measures for most developing countries. Except for energy-efficiency improvement and energy-system decarbonization, tropical developing countries with abundant forest resources should give priority to sustainable forest management, whereas other developing countries should pay more attention to enhancing methane capture rate and reducing recycling. These insights are crucial for developing net-zero strategies tailored to each country and achieving net-zero emissions by 2050 for the pulp and paper industry.

Global methane emissions from rivers and streams.

Methane (CH4) is a potent greenhouse gas and its concentrations have tripled in the atmosphere since the industrial revolution. There is evidence that global warming has increased CH4 emissions from freshwater ecosystems1,2, providing positive feedback to the global climate. Yet for rivers and streams, the controls and the magnitude of CH4 emissions remain highly uncertain3,4. Here we report a spatially explicit global estimate of CH4 emissions from running waters, accounting for 27.9 (16.7-39.7) Tg CH4 per year and roughly equal in magnitude to those of other freshwater systems5,6. Riverine CH4 emissions are not strongly temperature dependent, with low average activation energy (EM = 0.14 eV) compared with that of lakes and wetlands (EM = 0.96 eV)1. By contrast, global patterns of emissions are characterized by large fluxes in high- and low-latitude settings as well as in human-dominated environments. These patterns are explained by edaphic and climate features that are linked to anoxia in and near fluvial habitats, including a high supply of organic matter and water saturation in hydrologically connected soils. Our results highlight the importance of land-water connections in regulating CH4 supply to running waters, which is vulnerable not only to direct human modifications but also to several climate change responses on land.

Net greenhouse gas balance of fibre wood plantation on peat in Indonesia.

Tropical peatlands cycle and store large amounts of carbon in their soil and biomass1-5. Climate and land-use change alters greenhouse gas (GHG) fluxes of tropical peatlands, but the magnitude of these changes remains highly uncertain6-19. Here we measure net ecosystem exchanges of carbon dioxide, methane and soil nitrous oxide fluxes between October 2016 and May 2022 from Acacia crassicarpa plantation, degraded forest and intact forest within the same peat landscape, representing land-cover-change trajectories in Sumatra, Indonesia. This allows us to present a full plantation rotation GHG flux balance in a fibre wood plantation on peatland. We find that the Acacia plantation has lower GHG emissions than the degraded site with a similar average groundwater level (GWL), despite more intensive land use. The GHG emissions from the Acacia plantation over a full plantation rotation (35.2 ± 4.7 tCO2-eq ha-1 year-1, average ± standard deviation) were around two times higher than those from the intact forest (20.3 ± 3.7 tCO2-eq ha-1 year-1), but only half of the current Intergovernmental Panel on Climate Change (IPCC) Tier 1 emission factor (EF)20 for this land use. Our results can help to reduce the uncertainty in GHG emissions estimates, provide an estimate of the impact of land-use change on tropical peat and develop science-based peatland management practices as nature-based climate solutions.

Methane formation driven by reactive oxygen species across all living organisms.

Methane (CH4), the most abundant hydrocarbon in the atmosphere, originates largely from biogenic sources1 linked to an increasing number of organisms occurring in oxic and anoxic environments. Traditionally, biogenic CH4 has been regarded as the final product of anoxic decomposition of organic matter by methanogenic archaea. However, plants2,3, fungi4, algae5 and cyanobacteria6 can produce CH4 in the presence of oxygen. Although methanogens are known to produce CH4 enzymatically during anaerobic energy metabolism7, the requirements and pathways for CH4 production by non-methanogenic cells are poorly understood. Here, we demonstrate that CH4 formation by Bacillus subtilis and Escherichia coli is triggered by free iron and reactive oxygen species (ROS), which are generated by metabolic activity and enhanced by oxidative stress. ROS-induced methyl radicals, which are derived from organic compounds containing sulfur- or nitrogen-bonded methyl groups, are key intermediates that ultimately lead to CH4 production. We further show CH4 production by many other model organisms from the Bacteria, Archaea and Eukarya domains, including in several human cell lines. All these organisms respond to inducers of oxidative stress by enhanced CH4 formation. Our results imply that all living cells probably possess a common mechanism of CH4 formation that is based on interactions among ROS, iron and methyl donors, opening new perspectives for understanding biochemical CH4 formation and cycling.

Non-syntrophic methanogenic hydrocarbon degradation by an archaeal species.

The methanogenic degradation of oil hydrocarbons can proceed through syntrophic partnerships of hydrocarbon-degrading bacteria and methanogenic archaea1-3. However, recent culture-independent studies have suggested that the archaeon 'Candidatus Methanoliparum' alone can combine the degradation of long-chain alkanes with methanogenesis4,5. Here we cultured Ca. Methanoliparum from a subsurface oil reservoir. Molecular analyses revealed that Ca. Methanoliparum contains and overexpresses genes encoding alkyl-coenzyme M reductases and methyl-coenzyme M reductases, the marker genes for archaeal multicarbon alkane and methane metabolism. Incubation experiments with different substrates and mass spectrometric detection of coenzyme-M-bound intermediates confirm that Ca. Methanoliparum thrives not only on a variety of long-chain alkanes, but also on n-alkylcyclohexanes and n-alkylbenzenes with long n-alkyl (C≥13) moieties. By contrast, short-chain alkanes (such as ethane to octane) or aromatics with short alkyl chains (C≤12) were not consumed. The wide distribution of Ca. Methanoliparum4-6 in oil-rich environments indicates that this alkylotrophic methanogen may have a crucial role in the transformation of hydrocarbons into methane.

Wetland emission and atmospheric sink changes explain methane growth in 2020.

Atmospheric methane growth reached an exceptionally high rate of 15.1 ± 0.4 parts per billion per year in 2020 despite a probable decrease in anthropogenic methane emissions during COVID-19 lockdowns1. Here we quantify changes in methane sources and in its atmospheric sink in 2020 compared with 2019. We find that, globally, total anthropogenic emissions decreased by 1.2 ± 0.1 teragrams of methane per year (Tg CH4 yr-1), fire emissions decreased by 6.5 ± 0.1 Tg CH4 yr-1 and wetland emissions increased by 6.0 ± 2.3 Tg CH4 yr-1. Tropospheric OH concentration decreased by 1.6 ± 0.2 per cent relative to 2019, mainly as a result of lower anthropogenic nitrogen oxide (NOx) emissions and associated lower free tropospheric ozone during pandemic lockdowns2. From atmospheric inversions, we also infer that global net emissions increased by 6.9 ± 2.1 Tg CH4 yr-1 in 2020 relative to 2019, and global methane removal from reaction with OH decreased by 7.5 ± 0.8 Tg CH4 yr-1. Therefore, we attribute the methane growth rate anomaly in 2020 relative to 2019 to lower OH sink (53 ± 10 per cent) and higher natural emissions (47 ± 16 per cent), mostly from wetlands. In line with previous findings3,4, our results imply that wetland methane emissions are sensitive to a warmer and wetter climate and could act as a positive feedback mechanism in the future. Our study also suggests that nitrogen oxide emission trends need to be taken into account when implementing the global anthropogenic methane emissions reduction pledge5.

Borgs are giant genetic elements with potential to expand metabolic capacity.

Anaerobic methane oxidation exerts a key control on greenhouse gas emissions1, yet factors that modulate the activity of microorganisms performing this function remain poorly understood. Here we discovered extraordinarily large, diverse DNA sequences that primarily encode hypothetical proteins through studying groundwater, sediments and wetland soil where methane production and oxidation occur. Four curated, complete genomes are linear, up to approximately 1 Mb in length and share genome organization, including replichore structure, long inverted terminal repeats and genome-wide unique perfect tandem direct repeats that are intergenic or generate amino acid repeats. We infer that these are highly divergent archaeal extrachromosomal elements with a distinct evolutionary origin. Gene sequence similarity, phylogeny and local divergence of sequence composition indicate that many of their genes were assimilated from methane-oxidizing Methanoperedens archaea. We refer to these elements as 'Borgs'. We identified at least 19 different Borg types coexisting with Methanoperedens spp. in four distinct ecosystems. Borgs provide methane-oxidizing Methanoperedens archaea access to genes encoding proteins involved in redox reactions and energy conservation (for example, clusters of multihaem cytochromes and methyl coenzyme M reductase). These data suggest that Borgs might have previously unrecognized roles in the metabolism of this group of archaea, which are known to modulate greenhouse gas emissions, but further studies are now needed to establish their functional relevance.

Diversity and Evolution of Methane-Related Pathways in Archaea.

Methane is one of the most important greenhouse gases on Earth and holds an important place in the global carbon cycle. Archaea are the only organisms that use methanogenesis to produce energy and rely on the methyl-coenzyme M reductase complex (Mcr). Over the last decade, new results have significantly reshaped our view of the diversity of methane-related pathways in the Archaea. Many new lineages that synthesize or use methane have been identified across the whole archaeal tree, leading to a greatly expanded diversity of substrates and mechanisms. In this review, we present the state of the art of these advances and how they challenge established scenarios of the origin and evolution of methanogenesis, and we discuss the potential trajectories that may have led to this strikingly wide range of metabolisms.

Anaerobic Degradation of Alkanes by Marine Archaea.

Alkanes are saturated apolar hydrocarbons that range from their simplest form, methane, to high-molecular-weight compounds. Although alkanes were once considered biologically recalcitrant under anaerobic conditions, microbiological investigations have now identified several microbial taxa that can anaerobically degrade alkanes. Here we review recent discoveries in the anaerobic oxidation of alkanes with a specific focus on archaea that use specific methyl coenzyme M reductases to activate their substrates. Our understanding of the diversity of uncultured alkane-oxidizing archaea has expanded through the use of environmental metagenomics and enrichment cultures of syntrophic methane-, ethane-, propane-, and butane-oxidizing marine archaea with sulfate-reducing bacteria. A recently cultured group of archaea directly couples long-chain alkane degradation with methane formation, expanding the range of substrates used for methanogenesis. This article summarizes the rapidly growing knowledge of the diversity, physiology, and habitat distribution of alkane-degrading archaea.

Rapid microbial methanogenesis during CO2 storage in hydrocarbon reservoirs.

Carbon capture and storage (CCS) is a key technology to mitigate the environmental impact of carbon dioxide (CO2) emissions. An understanding of the potential trapping and storage mechanisms is required to provide confidence in safe and secure CO2 geological sequestration1,2. Depleted hydrocarbon reservoirs have substantial CO2 storage potential1,3, and numerous hydrocarbon reservoirs have undergone CO2 injection as a means of enhanced oil recovery (CO2-EOR), providing an opportunity to evaluate the (bio)geochemical behaviour of injected carbon. Here we present noble gas, stable isotope, clumped isotope and gene-sequencing analyses from a CO2-EOR project in the Olla Field (Louisiana, USA). We show that microbial methanogenesis converted as much as 13-19% of the injected CO2 to methane (CH4) and up to an additional 74% of CO2 was dissolved in the groundwater. We calculate an in situ microbial methanogenesis rate from within a natural system of 73-109 millimoles of CH4 per cubic metre (standard temperature and pressure) per year for the Olla Field. Similar geochemical trends in both injected and natural CO2 fields suggest that microbial methanogenesis may be an important subsurface sink of CO2 globally. For CO2 sequestration sites within the environmental window for microbial methanogenesis, conversion to CH4 should be considered in site selection.

Metallaphotoredox-enabled deoxygenative arylation of alcohols.

Metal-catalysed cross-couplings are a mainstay of organic synthesis and are widely used for the formation of C-C bonds, particularly in the production of unsaturated scaffolds1. However, alkyl cross-couplings using native sp3-hybridized functional groups such as alcohols remain relatively underdeveloped2. In particular, a robust and general method for the direct deoxygenative coupling of alcohols would have major implications for the field of organic synthesis. A general method for the direct deoxygenative cross-coupling of free alcohols must overcome several challenges, most notably the in situ cleavage of strong C-O bonds3, but would allow access to the vast collection of commercially available, structurally diverse alcohols as coupling partners4. We report herein a metallaphotoredox-based cross-coupling platform in which free alcohols are activated in situ by N-heterocyclic carbene salts for carbon-carbon bond formation with aryl halide coupling partners. This method is mild, robust, selective and most importantly, capable of accommodating a wide range of primary, secondary and tertiary alcohols as well as pharmaceutically relevant aryl and heteroaryl bromides and chlorides. The power of the transformation has been demonstrated in a number of complex settings, including the late-stage functionalization of Taxol and a modular synthesis of Januvia, an antidiabetic medication. This technology represents a general strategy for the merger of in situ alcohol activation with transition metal catalysis.

Unextractable fossil fuels in a 1.5 °C world.

Parties to the 2015 Paris Agreement pledged to limit global warming to well below 2 °C and to pursue efforts to limit the temperature increase to 1.5 °C relative to pre-industrial times1. However, fossil fuels continue to dominate the global energy system and a sharp decline in their use must be realized to keep the temperature increase below 1.5 °C (refs. 2-7). Here we use a global energy systems model8 to assess the amount of fossil fuels that would need to be left in the ground, regionally and globally, to allow for a 50 per cent probability of limiting warming to 1.5 °C. By 2050, we find that nearly 60 per cent of oil and fossil methane gas, and 90 per cent of coal must remain unextracted to keep within a 1.5 °C carbon budget. This is a large increase in the unextractable estimates for a 2 °C carbon budget9, particularly for oil, for which an additional 25 per cent of reserves must remain unextracted. Furthermore, we estimate that oil and gas production must decline globally by 3 per cent each year until 2050. This implies that most regions must reach peak production now or during the next decade, rendering many operational and planned fossil fuel projects unviable. We probably present an underestimate of the production changes required, because a greater than 50 per cent probability of limiting warming to 1.5 °C requires more carbon to stay in the ground and because of uncertainties around the timely deployment of negative emission technologies at scale.

Equity is more important for the social cost of methane than climate uncertainty.

The social cost of methane (SC-CH4) measures the economic loss of welfare caused by emitting one tonne of methane into the atmosphere. This valuation may in turn be used in cost-benefit analyses or to inform climate policies1-3. However, current SC-CH4 estimates have not included key scientific findings and observational constraints. Here we estimate the SC-CH4 by incorporating the recent upward revision of 25 per cent to calculations of the radiative forcing of methane4, combined with calibrated reduced-form global climate models and an ensemble of integrated assessment models (IAMs). Our multi-model mean estimate for the SC-CH4 is US$933 per tonne of CH4 (5-95 per cent range, US$471-1,570 per tonne of CH4) under a high-emissions scenario (Representative Concentration Pathway (RCP) 8.5), a 22 per cent decrease compared to estimates based on the climate uncertainty framework used by the US federal government5. Our ninety-fifth percentile estimate is 51 per cent lower than the corresponding figure from the US framework. Under a low-emissions scenario (RCP 2.6), our multi-model mean decreases to US$710 per tonne of CH4. Tightened equilibrium climate sensitivity estimates paired with the effect of previously neglected relationships between uncertain parameters of the climate model lower these estimates. We also show that our SC-CH4 estimates are sensitive to model combinations; for example, within one IAM, different methane cycle sub-models can induce variations of approximately 20 per cent in the estimated SC-CH4. But switching IAMs can more than double the estimated SC-CH4. Extending our results to account for societal concerns about equity produces SC-CH4 estimates that differ by more than an order of magnitude between low- and high-income regions. Our central equity-weighted estimate for the USA increases to US$8,290 per tonne of CH4 whereas our estimate for sub-Saharan Africa decreases to US$134 per tonne of CH4.

Global and regional drivers of land-use emissions in 1961-2017.

Historically, human uses of land have transformed and fragmented ecosystems1,2, degraded biodiversity3,4, disrupted carbon and nitrogen cycles5,6 and added prodigious quantities of greenhouse gases (GHGs) to the atmosphere7,8. However, in contrast to fossil-fuel carbon dioxide (CO2) emissions, trends and drivers of GHG emissions from land management and land-use change (together referred to as 'land-use emissions') have not been as comprehensively and systematically assessed. Here we present country-, process-, GHG- and product-specific inventories of global land-use emissions from 1961 to 2017, we decompose key demographic, economic and technical drivers of emissions and we assess the uncertainties and the sensitivity of results to different accounting assumptions. Despite steady increases in population (+144 per cent) and agricultural production per capita (+58 per cent), as well as smaller increases in emissions per land area used (+8 per cent), decreases in land required per unit of agricultural production (-70 per cent) kept global annual land-use emissions relatively constant at about 11 gigatonnes CO2-equivalent until 2001. After 2001, driven by rising emissions per land area, emissions increased by 2.4 gigatonnes CO2-equivalent per decade to 14.6 gigatonnes CO2-equivalent in 2017 (about 25 per cent of total anthropogenic GHG emissions). Although emissions intensity decreased in all regions, large differences across regions persist over time. The three highest-emitting regions (Latin America, Southeast Asia and sub-Saharan Africa) dominate global emissions growth from 1961 to 2017, driven by rapid and extensive growth of agricultural production and related land-use change. In addition, disproportionate emissions are related to certain products: beef and a few other red meats supply only 1 per cent of calories worldwide, but account for 25 per cent of all land-use emissions. Even where land-use change emissions are negligible or negative, total per capita CO2-equivalent land-use emissions remain near 0.5 tonnes per capita, suggesting the current frontier of mitigation efforts. Our results are consistent with existing knowledge-for example, on the role of population and economic growth and dietary choice-but provide additional insight into regional and sectoral trends.

A hybrid photocatalytic system enables direct glucose utilization for methanogenesis.

Integration of methanogenic archaea with photocatalysts presents a sustainable solution for solar-driven methanogenesis. However, maximizing CH4 conversion efficiency remains challenging due to the intrinsic energy conservation and strictly restricted substrates of methanogenic archaea. Here, we report a solar-driven biotic-abiotic hybrid (biohybrid) system by incorporating cadmium sulfide (CdS) nanoparticles with a rationally designed methanogenic archaeon Methanosarcina acetivorans C2A, in which the glucose synergist protein and glucose kinase, an energy-efficient route for glucose transport and phosphorylation from Zymomonas mobilis, were implemented to facilitate nonnative substrate glucose for methanogenesis. We demonstrate that the photo-excited electrons facilitate membrane-bound electron transport chain, thereby augmenting the Na+ and H+ ion gradients across membrane to enhance adenosine triphosphate (ATP) synthesis. Additionally, this biohybrid system promotes the metabolism of pyruvate to acetyl coenzyme A (AcCoA) and inhibits the flow of AcCoA to the tricarboxylic acid (TCA) cycle, resulting in a 1.26-fold augmentation in CH4 production from glucose-derived carbon. Our results provide a unique strategy for enhancing methanogenesis through rational biohybrid design and reprogramming, which gives a promising avenue for sustainably manufacturing value-added chemicals.

Structural and mechanistic basis of the central energy-converting methyltransferase complex of methanogenesis.

Methanogenic archaea inhabiting anaerobic environments play a crucial role in the global biogeochemical material cycle. The most universal electrogenic reaction of their methane-producing energy metabolism is catalyzed by N    5-methyl-tetrahydromethanopterin: coenzyme M methyltransferase (MtrABCDEFGH), which couples the vectorial Na+ transport with a methyl transfer between the one-carbon carriers tetrahydromethanopterin and coenzyme M via a vitamin B12 derivative (cobamide) as prosthetic group. We present the 2.08 Šcryo-EM structure of Mtr(ABCDEFG)3 composed of the central Mtr(ABFG)3 stalk symmetrically flanked by three membrane-spanning MtrCDE globes. Tetraether glycolipids visible in the map fill gaps inside the multisubunit complex. Putative coenzyme M and Na+ were identified inside or in a side-pocket of a cytoplasmic cavity formed within MtrCDE. Its bottom marks the gate of the transmembrane pore occluded in the cryo-EM map. By integrating Alphafold2 information, functionally competent MtrA-MtrH and MtrA-MtrCDE subcomplexes could be modeled and thus the methyl-tetrahydromethanopterin demethylation and coenzyme M methylation half-reactions structurally described. Methyl-transfer-driven Na+ transport is proposed to be based on a strong and weak complex between MtrCDE and MtrA carrying vitamin B12, the latter being placed at the entrance of the cytoplasmic MtrCDE cavity. Hypothetically, strongly attached methyl-cob(III)amide (His-on) carrying MtrA induces an inward-facing conformation, Na+ flux into the membrane protein center and finally coenzyme M methylation while the generated loosely attached (or detached) MtrA carrying cob(I)amide (His-off) induces an outward-facing conformation and an extracellular Na+ outflux. Methyl-cob(III)amide (His-on) is regenerated in the distant active site of the methyl-tetrahydromethanopterin binding MtrH implicating a large-scale shuttling movement of the vitamin B12-carrying domain.

Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.