"Negative trends on the ground have the potential to create an irreversible one-state reality that is incompatible with realising the legitimate national, historic and democratic aspirations of both Israelis and Palestinians," Guterres told a UN meeting of a committee on Palestinian rights.
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The UN chief said the global consensus on settling the Israeli-Palestinian conflict "could be eroding, making effective concerted action more difficult to achieve, at a time when it is more important than ever."
The Middle East peace process was upended when US President Donald Trump recognised Jerusalem as Israel's capital, ignoring the internationally-held view that the status of the holy city would be decided in peace negotiations.
The General Assembly adopted a resolution last month rejecting the US decision by a vote of 128 to nine with 35 abstentions.
The United States has also cut back its funding to the UN agency for Palestinian refugees (UNRWA), prompting Guterres to appeal to countries to step in to fill the gap.
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Israel's ongoing construction of settlements in the occupied Palestinian territories, violent attacks and the humanitarian crisis in Gaza are dimming prospects for a long-term peace, said the UN chief.
"There is no Plan B," Guterres told the meeting. "A two-state solution is the only way to achieve the inalienable rights of the Palestinian people and secure a sustainable solution to the conflict."
Palestinian president Mahmud Abbas is due to address the UN Security Council later this month after US Ambassador Nikki Haley said he lacked the courage needed for a peace deal.
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