While substantial progress has been made to improve our understanding of biogenic isoprene emissions under unstressed conditions, large uncertainties remain with respect to isoprene emissions under stressed conditions. Here, we use the US Drought Monitor (USDM) as a weekly drought severity index and tropospheric columns of formaldehyde (HCHO), the key product of isoprene oxidation, retrieved from the Ozone Monitoring Instrument (OMI) to derive top-down constraints on the response of summertime isoprene emissions to drought stress in the southeastern United States (SE US), a region of high isoprene emissions that is also prone to drought. OMI HCHO column density is found to be 6.7 % (mild drought) to 23.3 % (severe drought) higher than that under non-drought conditions. A global chemical transport model, GEOS-Chem, with version 2.1 of the Model of Emissions of Gases and Aerosols from Nature (MEGAN2.1) emission algorithm can simulate this direction of change, but the simulated increases at the corresponding drought levels are 1.1–1.5 times that of OMI HCHO, suggesting the need for a drought-stress algorithm in the model. By minimizing the model–OMI differences in HCHO to temperature sensitivity under different drought levels, we derived a top-down drought stress factor (γ_{d_OMI}) in GEOS-Chem that parameterizes using water stress and temperature. The algorithm led to an 8.6 % (mild drought) to 20.7 % (severe drought) reduction in isoprene emissions in the SE US relative to the simulation without it. With γ_{d_OMI} the model predicts a nonlinear increasing trend in isoprene emissions with drought severity that is consistent with OMI HCHO and a single site's isoprene flux measurements. Compared with a previous drought stress algorithm derived from the latter, the satellite-based drought stress factor performs better with respect to capturing the regional-scale drought–isoprene responses, as indicated by the near-zero mean bias between OMI and simulated HCHO columns under different drought conditions. The drought stress algorithm also reduces the model's high bias in organic aerosol (OA) simulations by 6.60 % (mild drought) to 11.71 % (severe drought) over the SE US compared to the no-stress simulation. The simulated ozone response to the drought stress factor displays a spatial disparity due to the isoprene-suppressing effect on oxidants, with an <1 ppb increase in O₃ in high-isoprene regions and a 1–3 ppbv decrease in O₃ in low-isoprene regions. This study demonstrates the unique value of exploiting long-term satellite observations to develop empirical stress algorithms on biogenic emissions where in situ flux measurements are limited.

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