There is no doubt that chronic gastroesophageal reflux disease increases the risk of esophageal adenocarcinoma (EAC) by several fold , and some relationships between reflux disease–mediated inflammation and oncogenic processes have been explored; however, the precise interconnections between the immune response and genomic instabilities underlying these pathologic processes only now are emerging. Furthermore, the precise cell of origin of the precancerous stages associated with EAC development, Barrett’s esophagus, be it cardia resident or embryonic remnant, may shape our interpretation of the likely immune drivers. This review integrates the current collective knowledge of the immunology underlying EAC development and outlines a framework connecting proinflammatory pathways, such as those mediated by interleukin 1β, tumor necrosis factor α, leukemia inhibitory factor, interleukin 6, signal transduction and activator of transcription 3, nuclear factor-κB, cyclooxygenase-2, and transforming growth factor β, with oncogenic pathways in the gastroesophageal reflux disease–Barrett’s esophagus–EAC cancer sequence. Further defining these immune and molecular railroads may show a map of the routes taken by gastroesophageal cells on their journey toward EAC tumor phylogeny. The selective pressures applied by this immune-induced journey likely impact the phenotype and genotype of the resulting oncogenic destination and further exploration of lesser-defined immune drivers may be useful in future individualized therapies or enhanced selective application of recent immune-driven therapeutics. Although EAC has affected mainly Western nations, the global spread of a high-calorie, cholesterol-rich diet has increased the occurrence of both abdominal obesity and gastroesophageal reflux disease (GERD): 2 factors that increase the risk of EAC by several-fold.The transient yet long-term exposure of esophageal tissue by gastric contents resulting from GERD, in addition to the accompanying immune response, has been theorized as a key developmental driver of BE, a potentially premalignant condition highly associated with EAC. As a type of intestinal metaplasia, BE is characterized by the replacement of stratified squamous epithelium with simple columnar epithelium that overlies mucous-secreting glands. Evidence from animal models, human cell lines, and patient-derived tissues has shown several potential cellular origins of BE. These include esophageal progenitor cells from either the basal squamous epithelium or in ductal cells of submucosal glands, squamocolumnar junction, gastric cardia, or bone marrow,,IL1B gene along the esophageal disease spectrum has trended toward nonsignificant associations. Nonetheless, a histologic inflammatory gradient has been observed in BE, defined by higher levels of IL1β and IL8, and was lowest at the esophageal z-line and progressively higher toward the new squamocolumnar junction of the BE lesion distal from the gastroesophageal junction (GEJ).,Homo sapiens, canine, and porcine.,+ cells negative for leucine rich repeat containing G protein-coupled receptor 5 (LGR5) at the murine GEJ were more susceptible to oncogenic transformation to GEJ carcinoma, by inactivation of tumor-suppressor genes Trp53 and Rb1, than their antral cousins. Similarly, KRASG12D- and p53mut-dependent transformation of KRT15+ cells at the murine squamocolumnar junction (SCJ) was higher than observed in the regions distal from the SCJ.,-CD44+ cells, warrants critical analysis. In canine reflux models, the presence of squamous barriers to proximal migration of columnar epithelium was not capable of inhibiting columnar metaplasia formation.IL1β is a proinflammatory cytokine that plays an important role in the initiation of the innate immune response.,,,,,,,71TNFα initially was noted for its cytotoxic effects on tumor cells; however, further studies elucidated both apoptotic and anti-apoptotic functions in the context of inflammatory responses.,APC gene results in overactive β-catenin signaling and subsequent promotion of cancer stemness in colonic epithelial cells.,,The proinflammatory role of TNFα has been implicated in chronic inflammation underlying the BE–high-grade dysplasia (HGD)–EAC progression.,,,,,97The NF-κB transcription factor is central to the proinflammatory response, cellular proliferation, and metastasis associated with the development and progression of various human cancers, including EAC.,,,The inflammatory response to reflux stress can be prompted through numerous means, not all of which may be through the caustic damage initiated by gastric bile acids and subsequent innate responses. Nonapoptotic concentrations of bile acids and minor changes in pH have been shown to result in the activation of NF-κB through the degradation of inhibitory proteins such as IκBα in esophageal epithelial cells, subsequently inducing the expression and release of cytokines, such as IL8 and IL6, and the prostaglandin-synthesizing enzyme COX2,,PTGS2) gene expression in a wide variety of esophageal cell lines.,,,+ population at the murine SCJ and additionally showed, using both murine and organoid experimentation, that this may be mediated through affects on COX2 activity.Prostaglandins are lipid autacoids whose levels increase at sites of wounding or infection and may have both inflammatory and suppressive roles mediated by G-protein–coupled receptor binding in early and late phases of inflammation. Notably, prostaglandins are involved in some of the more visible signs of inflammation such as redness, swelling, and pain. The COX1 and COX2 enzymes together with tissue-specific isomerases convert arachidonic acid into a variety of prostanoids. Although the COX2 synthase, traditionally under the control of NF-κB, mediates the synthesis of many prostaglandin isoforms from arachidonic acid, the most prevalently studied in the context of adenocarcinogenesis is prostaglandin E2 (PGE2).,,VEGF-A, TGFβ,Bcl-xL, and Mcl-1.,,118,,,Studies have suggested that intrinsic, aberrant STAT3 activation upon BE–HGD–EAC development increases the ability of these cells to evade apoptosis in response to low pH and/or bile acid–rich environments.,,,Recent RNA sequencing expression studies from a variety of patient-derived BE, HGD, and EAC tissues has shown a significantly large increase in tissue IL6 expression along the adenocarcinogenesis sequence.,A higher M2/M1 ratio of tumor-associated macrophages (TAMs) is associated with increased EAC tumor metastatic potential, possibly owing to the immunosuppressive capacities of M2-type TAMs, which drive tumor immune escape.,,,,,,The cytokine TGFβ is a pleiotropic regulator involved in epithelial and immune homeostasis; immune tolerance; and context-dependent effects on cellular differentiation, development, and tissue homeostasis.,,,,,,,,,,,,108,At steady-state, TGFβ maintains the homeostasis of peripheral CD4+ and CD8+ T-cell levels through a canonical signaling pathway. This is dependent on small mothers against decapentaplegic family member 3 (SMAD3), a receptor-regulated SMAD that mediates the suppression of prostimulatory IL2.,Complement component 1q (C1q) is a soluble protein complex acting as a key bridge between innate and adaptive immune responses.In the cancer TME, the complement system and its constituent components are proposed to be engaged in the antibody-mediated killing of targeted cancer cells, support chronic inflammatory states, or indeed hamper antitumor responses. Furthermore, some complement components have been observed to support tumor neoangiogenesis. Clinical data from a recent cohort of 134 colon, lung, lymphatic, and blood cancer patients, with circulating C1q levels higher than the 95th percentile, indicated a strong correlation between enriched blood C1q and post-treatment failure.,https://xcell.ucsf.edu/). From their analysis, both Th1 and Th2 signatures were significantly greater in EAC vs BE samples; however, unlike Kavanagh et al,,Characterizing the population of immune cells infiltrating the esophageal epithelium along BE-EAC progression may provide insight into the aims, resolution, and processing of the local inflammatory or immune response to environmental stressors such as GERD. Studies on the identity of immune cell infiltration in response to GERD and upon BE development are surprisingly scarce; however, they provide some initial insight to the cellular immune microenvironment that potentially shapes and perhaps drives the malignant transition of esophageal epithelium. Current evidence points tentatively towards dynamic populational shifts during this carcinogenic timeline, beginning as a predominantly proinflammatory CD4+ T-cell infiltrate that shifts to one that may be immunosuppressive in late-stage EAC. The proportion of Th1 and Th2 signatures have been used primarily to represent shifts between distinct tissue-immune environments, because Th1 cells primarily secrete IL2 and IFN-γ, whereas Th2 cells secrete IL4 and IL10.,Although previous studies have shown distinct shifts in immune cell infiltrate composition along BE adenocarcinogenesis, no studies have directly examined if these shifts may be influenced directly by reflux; however, there have been clinical studies examining the relationship between PPIs and eosinophilic esophagitis (EoE) that showed distinct changes in mucosal eosinophil populations post-treatment.From these studies, it is unclear how both the innate and adaptive immune infiltrate interact to contribute to the overall lesion milieu. Thus, simultaneous cytometric and cytokine paneling studies of higher-powered cohorts are required to determine this relationship and how they affect the overall immune outcome. Comparing normal squamous esophageal cells with BE and EAC, although still pertinent, may not be as important as comparisons with the GEJ, from which it now is suggested that BE emerges. A recent single-cell RNA sequencing and lineage tracing study proposed that BE arises from the gastric cardia, and that EAC arises from undifferentiated BE cell types.Although we have begun to understand and explain some of the potential origins of BE, the mechanisms through which GERD supports its emergence and its transition to adenocarcinoma remains elusive and yet still is guilty by association. It is likely that some aspects of acid and bile acid signaling play an important role in emergent genomic instability, but the impact of chronic or recurrent inflammation at the GEJ cannot be supplanted as a likely driver. The wider immunologic contributors to BE and EAC development have yet to be thoroughly defined, such as those provided by immune cells recruited during GERD, BE, and HGD. These aspects can be studied only from an associative context in clinical samples and have not been as tractable in murine models thus far. Therefore, this review limited its scope to cytokine-mediated signaling in the esophagus and its linkage with the emergence of oncogenic and metaplastic transformation from BE. The majority of the research reviewed herein has been performed using a variety of cell line models of esophageal signaling and tended to lean more upon EAC cell lines than that of normal squamous esophageal cell types. Furthermore, if the true origin of BE is from stem cells within the GEJ then the impact of cytokine signaling upon BE-associated differentiation markers in squamous cells becomes less relevant. Inflammatory signaling in the squamous esophagus, however, is still a key component of BE development whether directly or independently through chemotaxis of immune cells to the GEJ and consequent contributions to metaplasia. Regardless, our research community requires novel solutions, model systems, and platforms for exploring the cellular immunity beneath BE and EAC development that is directed by the cytokine milieu and clearly still an important contributor to metaplasia and dysplasia.,,conditional reprogramming,,,Investment in porcine and canine models in addition to the development of novel platforms may be needed to surmount the obstacles between fundamental basics sciences and translational medicine as it is applied to esophageal pathologies that are poorly modeled in the mouse. Older studies modeling metaplasia in the canine showed a more anatomically correct emergence in response to surgically induced reflux.In summary, defining the order of this paradoxic inflammatory pathway underlying BE–EAC may not be as critical as studying how, if, or when it reaches resolution and whether this resolution differs between normal esophagus, columnar BE lesions, dysplastic pathologies, and early cancers. To address these questions, we must rely on, and be informed by, the patient population and their continued engagement with research in addition to the continued development of in vitro organoid technologies and animal models of the BE–EAC transition.


What-if scenarios vary: conifer-broadleaf composition, harvesting, product breakouts, and decarbonisation of substituted energy and materials, to estimate 100-year GHG mitigation. Here we find forest growth rate is the most important determinant of cumulative mitigation by 2120, irrespective of whether trees are harvested. A national planting strategy of commercial forest could mitigate 1.64 Pg CO2e by 2120 (cumulative), compared with 0.54–1.72 Pg CO2e for planting only conservation forests, depending on species composition. Even after heavy discounting of future product substitution credits based on industrial decarbonisation projections, GHG mitigation from harvested stands typically surpasses unharvested stands. Commercial afforestation can deliver effective GHG mitigation that is robust to future decarbonisation pathways and wood uses.Afforestation is an important greenhouse gas (GHG) mitigation strategy but the efficacy of commercial forestry is disputed. Here, we calculate the potential GHG mitigation of a UK national planting strategy of 30,000 ha yr Afforestation is an important greenhouse gas (GHG) mitigation strategy but the efficacy of commercial (harvested) forestry is disputed. Here the authors apply dynamic life cycle assessment to show that new commercial conifer forests can achieve up to 269% more GHG mitigation than semi-natural forests, over 100 years. Afforestation on land spared from agriculture3 is proposed as an integral element of greenhouse gas (GHG) mitigation5, but mitigation efficacy is highly context specific and depends on, inter alia, climate, tree species, management and product substitution. In tropical regions, fast-growing commercial forests managed for wood production have been unfavourably compared to restoration of natural forest6 but these conclusions are not transferable to a temperate context. There remains a gap in evidence determining the most effective type of temperate forestry for achieving GHG mitigation. The role of sustainable wood harvesting is recognised in GHG mitigation strategies8 and could be enhanced through cascading use of wood9, but recent modelling indicates that future mitigation from product substitution will diminish owing to decarbonisation of substituted materials and energy11. In coniferous temperate forests, bioenergy harvest breakeven times can range from 30 to 70 years assuming coal is being replaced, depending on the scale of the assessment and whether the stands are damaged12. Meanwhile, dynamic life cycle assessment (LCA) studies indicate that it can take up to 100 years for CO2 released from current bioenergy generation to be fully compensated by forest regrowth14.Achieving the ambition of the Paris Agreement to limit global warming to 1.5 °C above pre-industrial levels requires rapid implementation of negative emissions technologies15 in the context of decarbonised material and energy systems4. We fill this gap through comparison of 100-year mitigation achieved by newly planted commercial and conservation  forests in the UK, a country with high afforestation potential17. Although prioritising GHG mitigation in afforestation strategies will involve complex trade-offs with other ecosystem services21, such as biodiversity conservation, the purpose of this paper is not to explore these. Rather, it aims to generate robust evidence on the efficacy of alternative afforestation options for the primary strategic aim of mitigating GHG emissions. We apply dynamic consequential LCA22 to 33 what-if scenarios representing a range of commercial Sitka spruce (Picea sitchensis) forests with different harvested wood product (HWP) value chains, and conservation forests, across representative growth rates, and in the context of different decarbonisation pathways  of hierarchical wood value chains2e ha−1 within a core decarbonisation pathway projected for the UK4 by 2120—up to 269% more mitigation than delivered by newly planted broadleaf conservation forests, and 17% more than achieved by leaving a newly planted fast-growing conifer forest unharvested. Harvesting reduces long-term terrestrial carbon storage by 61%, but this is more than offset by HWP carbon storage, and concrete and energy substitution—even with near total decarbonisation of the energy sector within the 100-year study horizon. Projected wide deployment of carbon capture and storage (CCS)4 contributes up to 45% of cumulative 100-year mitigation benefit, but also reduces the energy substitution credits realised by future wood energy. Consequently, the efficacy of mitigation is surprisingly similar between hierarchical and bioenergy uses of wood, and remarkably resilient to CCS deployment assumptions. To contextualise the results in a national planting strategy, we model the UK Committee on Climate Change recommended planting rate of 30,000 ha year−1 from 2020 to 2050. If this strategic target is met with commercial forests, it would cumulatively mitigate up to 1.64 Pg CO2e emissions by 2120, compared with 0.54 Pg CO2e for a semi-natural broadleaf conservation forest, or 1.09 Pg CO2e for an equal planting rate of 15,000 ha year−1 of each forest type. For UK forests and projected decarbonisation pathways, large-scale commercial afforestation could contribute strongly to GHG mitigation targets.Under typical conditions, one hectare of newly planted commercial forest could achieve cumulative GHG mitigation of up to 2.27 Gg CO2e ha−1, respectively  and concrete substitution in the Core context, at average growth rates  are based on the conservative assumption of a very gradual decline in the emission intensity of processing operations  and 269% (relative to 100% broadleaf) more GHG mitigation than conservation forests over a 100-year time horizon from establishment.Terrestrial carbon sequestration in semi-natural broadleaf, mixed conifer-broadleaf and fast-growing conifer conservation forests planted in 2020 equates to cumulative mitigation by 2120 of 0.62 (0.41–0.82), 1.30 (0.94–1.64) and 1.94 (1.30–2.58) Gg CO2e at default yield  and YC22 Bioenergy (Core), respectively  context could reduce cumulative national mitigation achieved by Hierarchical or Bioenergy wood use in 2120 by 5% or 2%, respectively  of cumulative GHG mitigation by 2120 for Core and Further Ambition contexts (YC 18), respectively. Reducing product substitution by 50% would reduce cumulative GHG mitigation by 5% or 11% for Core or Further Ambition contexts, respectively  accounts for 0.12–0.32 Pg CO1 even with projected decarbonisation of marginal materials and energy that are likely to be substituted by HWPs in the future. These results counter the conclusions of recent studies questioning the climate credentials of commercial forestry23. Our study demonstrates the importance of considering multiple stages of hierarchical wood use, considering, inter alia, consistent time-dependent substitution factors and CCS deployment based on published projections24. However, we do find that at equivalent growth rates, commercial forests lag unharvested conservation forests in cumulative GHG mitigation until just before the second harvest cycle .New evidence presented in this paper emphasises the efficacy of commercial forestry for GHG mitigation, and its resilience to future decarbonisation pathways and wood uses, highlighting the effective and reliable contribution that commercial forestry could make towards the Paris Agreement26. In this study, the vast majority of product substitution credits attributable to new forest planting are heavily discounted because they arise over 50 years into the future (after first main harvest) when decarbonisation projections indicate much lower emission intensities for substituted energy and materials —requiring a rate of planting 4.6 times higher, and continuing 20 years longer, than the 30,000 ha year−1 over 30 years considered in our study based on UK Committee on Climate Change recommendations4. Although a large area, this would bring total UK forest cover to around 42%, close to the European average of 40%34. Whilst purpose-grown bioenergy crops could deliver more rapid fossil fuel substitution using less land33, commercial forests combine the provision of high-quality materials into the circular economy with the delivery of multiple ecosystem services20, including medium-term climate regulation by terrestrial C storage35 and HWP C storage in the decades before BECCS is anticipated to become widely deployed31 , or left in the ground to maximise terrestrial C storage. The latter option can be chosen late in the forestry cycle in response to relevant market, environmental and/or policy signals. Commercial forestry therefore provides a robust strategy for GHG mitigation across a wide range of future contexts, at least in temperate zones, and merits a prominent role in climate policies, including nationally determined contributions under the Paris Agreement, and the forthcoming EU Forest Strategy36.Commercial afforestation can deliver significantly greater GHG mitigation than semi-natural afforestation largely due to the higher growth rate of conifers. Commercial investment in afforestation is based on the expectation of timber harvest and, to match current timber markets in the UK and the benefit of earlier harvest of faster-growing tree species, this generally leads to the planting of conifer rather than broadleaved species. Thus, faster-growing commercial forests deliver more, and longer-term, GHG mitigation than slower growing semi-natural forests. Depending on future decarbonisation and technology contexts, market demand and environmental risks, high yielding conifer forests could be harvested36. We applied a 100-year cut-off to our analysis to maintain a realistic time horizon for climate policy decision making, and to avoid deeply uncertain marginal technologies beyond this time horizon. A longer time horizon is likely to favour harvested commercial forests owing to saturating carbon sequestration in conservation forests . In regions  with slower tree growth rates and longer forestry cycles, leaving wood unharvested could be a better mitigation option over the next centurysts Fig. . There i5. Rather than limiting the area of commercial forests in favour of semi-natural forests6, more emphasis should be placed on rapid deployment of both forest types, and on the cascading use of harvested wood to derive maximum economic and mitigation value. Although our modelled commercial forestry system is 100% Sitka spruce, single species forests are not the only commercial option, and there is increasing support for mixed-species conifer forests (or conifer-broadleaf mixtures), under sustainable forest management to deliver both a high yield of wood products and other ecosystem services41. Diversification of commercial forestry could also enhance resilience to pests, diseases and climate change effects44. Nabuurs et al.8 argue for policy changes to encourage such ‘climate-smart forestry’, claiming it could deliver an extra 441 Mt CO2e year−1 mitigation across Europe by 2050. National afforestation strategies should promote a portfolio of commercial, conservation and agroforestry systems tailored to local conditions and adapted to climate change45, in order to deliver the range of ecosystem services required by society, in addition to GHG mitigation46. To achieve this there is a strong case to increase the 30,000 ha year−1 UK afforestation area target of the Committee on Climate Change, which is very modest in the context of international ambitions for increased tree canopy cover, such as the 0.9 billion hectares identified by Bastin et al.47, or indeed the EU Forest Strategy objective to plant 3 billion trees by 203036. Successful forest policy will also need to integrate social outcomes, and engage local stakeholders in strategic planning41.Whilst results in this paper demonstrate the comparatively high long-term GHG mitigation efficacy of commercial forests compared with unharvested conservation forests, it is imperative to note that commercial and conservation forests deliver different suites of important ecosystem services and should be considered complementary and not conflicting land uses48. Whilst sustainable intensification3 and curtailed demand for livestock products49 are projected to free up substantial land for afforestation in the UK and elsewhere over coming decades, our results reveal the urgency of commencing a programme of large-scale tree planting if afforestation is to significantly contribute to Paris Agreement targets for the second half of this century48.We conclude that fast-growing tree species should be a major component of national afforestation strategies in order to achieve ambitious GHG mitigation targets. Commercial investment will favour such high production forests of species that produce timber matching market demand. The GHG mitigation potential of commercial forestry is robust against future decarbonisation scenarios, and will continue to deliver mitigation well beyond the 100-year timeframe considered in this study, when conservation systems have reached their peak capacity. Furthermore, commercial forestry can deliver similar long-term mitigation when wood is used in either hierarchical or bioenergy value chains, potentially contributing to future circular bioeconomy, energy security and carbon removal objectives as required at the time of harvest. However, it takes time to establish large areas of new forest. In addition to the time lag between forest establishment and GHG mitigation, especially pronounced when considering mitigation from commercial forest hierarchical value chains, there is a time lag in implementation of national afforestation policies owing to constrained planting rates3 ha−1 year−1: ‘yield class’) and HWP value chains  GHG mitigation efficacy resulting from the establishment of commercial forests and conservation forests on grassland in the UK (baseline). We modelled 33 scenarios representing common temperate commercial and conservation forestry typologies, tree growth rates (m00-year G3 ha−1 year−1 (range 12–24)50, with intermediate forest thinning in year 21 of each rotation when 36% of the harvestable material is removed in HWP. Clear-fell harvest is implemented in year 50 (a conservative average for this species in UK conditions), followed by immediate replanting, enabling a second clear-fell in year 100. Non-merchantable biomass was assumed to be left to decay on site. Two predominant types of wood value chain were modelled, representing different wood use strategies: (i) a Hierarchical wood use strategy, with wood flow based on UK statistics and data from mills that maximise the value of wood products, and embodying the waste hierarchy51  a Bioenergy wood use strategy, in which high-value sawn wood is used in the construction sector , but all other wood, and end-of-life construction wood, is used for electricity generation to contribute to bioenergy targets4. Dynamic assessment of incurred and avoided emissions during future wood harvest and processing operations, construction material and fossil fuel substitution, and BECCS deployment, was applied based on decadal progression of marginal technologies in line with two sets of projections made by the UK Committee on Climate Change: ‘Core’ and ‘Further Ambition’ pathways4—detailed in Table marginal source of dispatchable energy generation well into the future, especially for industrial heat, despite renewable energy technologies predominating24. Very few studies to date consider the timing of GHG emissions41 and avoided GHG emissions in this way.Commercial forestry was based on conifer (Sitka spruce) forests, with a conservative default YC of 18 m1 range 1–2450, wi7. We represented a diverse range of possible conservation (unharvested) forest types based on different ratios of conifer  to broadleaf  trees  and 100% broadleaved (4) are for the same site conditions.Forests may be established for varying conservation objectives, from habitat provisioning to terrestrial carbon storagees Table . The 100−1 planted from 2020 to 2050 as per UK climate recommendations17 on 900,000 ha of lower-quality grassland that could be taken out of livestock production through intensification3 and/or reduced market demand for livestock products49. We assume that social and political change will lead to sufficient land being available, therefore, avoided GHG emissions from reduced livestock production or additional emissions from livestock production displacement are not considered. Analyses were cut off at 2120 in both scenarios, representing a maximum time horizon for climate policy. Climate change impacts on forest productivity were not included due to the already high complexity of the scenarios.Scenarios were analysed at two scales: 1 ha planted in 2020, and a national scenario of 30,000 ha year22 to evaluate the GHG emissions balance of afforesting one hectare of grassland in the UK, accounting for terrestrial (soil and biomass) carbon storage, HWP carbon storage, substitution of materials and fossil fuels and long-term sequestration of biogenic carbon via future deployment of BECCS, over a 100-year period. Expanded LCA boundaries  recycling and disposal of retired HWPs, including via (ix). The production and transport of all material and energy inputs were accounted for, as were the construction or manufacture of infrastructure and capital equipment. Full life cycle inventories are provided in Supplementary Data 54, harvest data from over 2,000 ha of commercially managed forests, data form a commercial sawmill that maximises sawn wood output, national recycling data55 and timber-use statistics56—elaborated in S1. Given the focus of this paper on GHG mitigation, only the global warming potential (GWP100) impact category was evaluated, expressed as kg CO2e. Limitations are explored in the Discussion.We applied dynamic consequential LCAies Fig.  encompas54, because it complies with the Intergovernmental Panel on Climate Change guidance53, was developed for similar climate conditions to the UK and provides default volume to biomass equations for Sitka spruce and Douglas fir (which are native to Canada), and genus equations for the other species in this study. It was parameterised using best-fit yield tables from Forest Yield, the standard yield model for forest management in the UK50. For conservation forests, aggregate group YCs were calculated based on weighted mean YCs for the species mixes described in Table 57. Detailed material flows are presented in Supplementary Data Forest growth, decay and harvest volumes were calculated using the Carbon Budget Model for the Canadian Forest Sector CBM-CFS3)54, becau58 using OpenLCA v1.7.4 and scaled in Microsoft Excel using the HWP material flow  in proportions calculated according to UK recycling statsistics55  into an area of timber-framed wall using industry standard design: 0.0175 m3 of timber per 1 m2 wall  wall with 10-mm jointing in typical UK house construction. Avoided emissions were then calculated using emission factors from Ecoinvent for the manufacture of concrete blocks, sand and cement. Projected decarbonisation of the cement sector is represented in Core and Further Ambition contexts  were taken from Ecoinvent unit processes27. This study presents a methodological approach that addresses key limitations by considering different value chains and dynamic product counterfactuals under different decarbonisation pathways. To further explore the complexity and uncertainty of future wood value chains, we modelled alternative product substitution assumptions to assess the sensitivity of model results to product substitution. Details of these are provided in S1 and Supplementary Data Recent papers have highlighted the uncertain assumptions inherent in wood product substitution estimatesFurther information on research design is available in the Supplementary InformationPeer Review FileDescription of Additional Supplementary FilesSupplementary Data 1Supplementary Data 2Supplementary Data 3Supplementary Data 4Supplementary Data 5Supplementary Data 6Supplementary Data 7Reporting Summary